Amphidinolide B: Total synthesis, structural investigation, and biological evaluation

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Amphidinolide B: Total Synthesis, Structural Investigation,

and Biological Evaluation

Liang Lu,^†Wei Zhang,^†Sangkil Nam,^‡,§David A. Horne,^‡Richard Jove,^‡and Rich G. Carter*^,†

^†Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States

^‡Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California 91010, United States

S

* Supporting Information

ABSTRACT: The total syntheses of amphidinolide B₁and the proposed

structure of amphidinolide B₂have been accomplished. Key aspects

of this work include the development of a practical, non-transition-

metal-mediated method for the construction of the C₁₃−C₁₅diene, the

identiﬁcation of α-chelation and dipole minimization models for

diastereoselective methyl ketone aldol reactions, the discovery of a

spontaneous Horner−Wadsworth−Emmons macrocyclization strategy,

and the development of a novel late stage method for construction of an

allylic epoxide moiety. The originally proposed structure for amphidino-

lide B₂and diastereomers thereof display potent antitumor activities with

IC₅₀values ranging from 3.3 to 94.5 nM against human solid and blood

tumor cells. Of the diﬀerent stereoisomers, the proposed structure of amphidinolide B₂is over 12-fold more potent than the

C_8,9-epimer and C₁₈-epimer in human DU145 prostate cancer cells. These data suggest that the epoxide stereochemistry is a

signiﬁcant factor for anticancer activity.

member of the amphidinolide family, demonstrating impressive

potency in early cancer screening [IC₅₀levels: L1210 murine

leukemia cell line (0.14 ng/mL),^2bhuman colon tumor HCT 116

cell line (0.12 μg/mL),^2cand KB cancer cell line (4.2 ng/mL)].^1f

In addition to the intriguing biological activity, macrolide 2 has

a compelling architecture with nine stereogenic centers embedded

within a 26-membered macrocycle including a reactive allylic

epoxide moiety at C₆−C₉and a highly substituted diene moiety

at C₁₃−C₁₅. Consequently, this target 2 has attracted con-

siderable synthetic attention from numerous laboratories⁷

including our own.⁸⁻¹⁰In 2008, we reported the ﬁrst total

syntheses of amphidinolide B₁(2) as well as the proposed structure

of amphidinolide B₂(3) which we established to be incorrect.⁴

INTRODUCTION

■

First reported in 1986, the amphidinolide family of natural

products has long captured the attention of the scientiﬁc

community.¹To date, over 30 members of this family have been

isolated.²Given their fascinating structures and diverse biological

activity, these targets have attracted considerable attention in

both the synthetic³⁻⁵and biological communities.⁶

From this diverse collection of compounds, the amphi-

dinolide B subfamily possesses some of the most intriguing

structural features and biological activity. Kobayashi and co-

workers reported the isolation of the 26-membered macrolide

(amphidinolide B) from the dinoﬂagellate Amphidinium sp. in

small amounts (Figure 1).^2bThe planar original structure was

proposed as compound 1. Subsequent reisolation by Shimizu

and co-workers as well as structure determination through X-ray

crystallographic analysis by Clardy and co-workers provided the

relative stereochemistry of amphidinolide B (which was renamed

amphidinolide B₁) as compound 2.^2cIn addition, the location

of the methyl moiety of the dienyl system was reassigned to the

C₁₅position. Absolute conﬁguration of 2 was later established

via degradation.^2dShimizu and co-workers also reported the

isolation of two related members of this family, amphidinolide B₂

(3) and B₃(4), and proposed their structures based on analogy to

2 and comparison of the NMR spectra. More recently, Kobayashi

and co-workers reported the isolation of additional members

of this subfamily, amphidinolide B₄and B₅(5 and 6)^2eas well as

amphidinolides B₆and B₇(not shown).^2fStructurally related

amphidinolides G and H [e.g., amphidinolide H₁(7) and

amphidinolide G₁(8)] have also been reported.^2p−rIn particular,

amphidinolide B₁(2) has proven to be the most cytotoxic

Subsequent to our eﬀorts, Furstner and co-workers published

̈

their synthesis of 2 in 2009⁵and more recently Nishiyama and

co-workers completed their total synthesis in 2012.¹¹It should be

noted that Furstner reported the ﬁrst syntheses of related

̈

amphidinolides G and H in 2007.^3aaHerein, we disclose a full

account of our work and the biological evaluation of synthesized

analogues of amphidinolide B.

RESULTS AND DISCUSSION

■

Our initial retrosynthetic strategy is shown in Scheme 1. We

intended to install the fragile allylic epoxide moiety at a late stage

from the corresponding C₇−C₉enone motif. Macrolactonization

of the corresponding seco acid 9 under Mitsunobu conditions¹²

could form the key 26-membered ring system. The C₈−C₉bond

Received: December 5, 2012

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Scheme 1. Initial Retrosynthetic Analysis of Amphidinolide B₁

Scheme 2. Synthesis of Diene Precursors

Figure 1. Amphidinolides B, G, and H.

would be accessible from a HWE oleﬁnation with the keto

phosphonate 11 and aldehyde 10. The C₁₈stereogenic center

could be constructed by a chelation-controlled aldol condensa-

tion between aldehyde 12 and α-benzyloxy ketone 13. The

aldehyde 12 would be derived from the styrenyl compound 14

through a regioselective oxidative cleavage. The diene could be

accessed from the coupling of an allylic metallo species such as 15

and the methyl ketone 16.

Synthesis of the nucleophilic components 24 and 25 and

styrenyl compound 16 are shown in Scheme 2. The methyl

ketone 16 could be prepared in four steps from ^L-lactic acid (17).

Using Seebach chemistry,¹³stereochemistry originally contained

in the hydroxyl acid 17 was transferred cleanly to the lactone 20

with high levels of diastereoselecitivity. Treatment of the lactone

with MeLi yielded the α-hydroxy methyl ketone which was

protected as its TES ether 16. For the nucelophilic component

15, we envisioned multiple options including phosphonate 25

and Peterson-type approaches (e.g., 24). Starting from the

commercially available oxazolidinone 21 and known iodide 22,¹⁴

Evans alkylation followed by reduction and protection generated

B

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the allyl silane 24. Bromination at C₁₄using NBS followed by

Arbuzov reaction generated the allyl phosphonate 25 in 55%

yield over two steps.

With the coupling partners in hand, we envisioned multiple

options for their combination (Scheme 3). One of the initial

While the vinyl silane product 27 is in theory still a viable

intermediate in the synthesis of the diene 26, we were unable to

facilitate the subsequent conversion to the target diene.¹⁸We

also explored a Sakurai-type approach¹⁹to C−C bond formation

using allyl silane 24. Treatment of 24 and 16 under a range of

Lewis acidic conditions (e.g., TMSOTf, BF₃·Et₂O, Me₂AlCl,

AlMe₃, SnCl₄) did not provide any of the desired coupled

material 28. Fortunately, treatment with freshly distilled TiCl₄

did facilitate the C₁₄−C₁₅bond construction in up to 65%

yield and 6:1 dr (stereochemistry at C₁₅undetermined). While

eﬀective, this reaction did prove to be scale dependent (typically

providing 50−65% yield at 0.65 mmol scale, but 20−30% yield at

2.0 mmol scale). Despite considerable eﬀort to ascertain the

nature of the scale dependence, we were unable to fully address

this shortcoming. Consequently, this transformation was often

run in parallel batches to bring through suﬃcient amounts of

material. Subsequent elimination of the tertiary alcohol 28 was

best facilitated using SOCl₂and pyridine in toluene at −78 °C to

yield the desired diene in near-quantitative yield as a 2.2:1 ratio of

diene regioisomers (rr) (26:29). The diene rr was not impacted

by use of a single C₁₅stereoisomer of alcohol 28. Use of alternate

conditions (e.g., MsCl, POCl₃, Tf₂O, Burgess reagent, Martin’s

sulfurane) led to no product formation or inferior levels of

regioselectivity. While these diene regioisomers 26 and 29 were

not readily separable by column chromatography, removal of the

silyl protecting group provided the corresponding regioisomeric

diols 30 and 31 that were separable.

Scheme 3. Synthesis of Diene

The functionalization of the polyene is shown in Scheme 4.

Mitsunobu-type conversion of the C₁₀alcohol into the

corresponding nitrile followed by silyl protection yielded 14.

Next, we required the selective functionalization of the C₁₈−C₁₉

alkene in the presence of the less sterically hindered 1,1-

disubstituted alkene at C₁₃and the more electron rich alkene at

C₁₄−C₁₅. We had hoped that regioselective dihydroxylation at

C₁₈−C₁₉could be possible by exploiting a π-stacking interaction

between the phenyl ring and aromatic systems present in

Sharpless ligands. While this sort of phenomenon has been used

previously to explain enhanced enantioselectivity²⁰and even

diastereoselectivity²¹in Sharpless asymmetric dihydroxylation,

we were unaware of prior examples to exploit purely a regio-

selective directing eﬀect. To our delight, the AD Mix β* [the *

denotion represents higher percentages of K₂OsO₄·2H₂O and

(DHQD)₂PHAL as compared to the commercial amounts]

provided excellent regioselectivity for the desired location. As

hypothesized, use of standard OsO₄/NMO conditions provided

a complex mixture of products. Interestingly, AD Mix α* also

proved to be a poor reagent of this transformation. While we can

rationalize the poor outcome of the ligandless system, a rational

for the reactivity diﬀerences between the pseudoenantiomeric

ligand systems is less obvious. One possible explanation may be

that the C₁₆stereocenter exerts a pronounced inﬂuence on the

conformation of the neighboring alkenes, resulting in a mismatched

interaction between the (DHQ)₂PHAL ligand in AD mix α and the

desired alkene. It is also clear that a conformational change occurs

between the unconjugated system 33 and the conjugated system

14, dihydroxylation of polyene 33 results in a regioselective

oxidation at C₁₈−C₁₉; however, the reaction does not show any

diastereoselectivity. Periodate cleavage under standard conditions

yielded the aldehydes 12 and 35.

approaches we explored was a phosphonate oleﬁnation strategy.

Unfortunately, using a range of bases (e.g., n-BuLi, t-BuLi, s-BuLi,

KHMDS) we were unable to facilitate the oleﬁnation. An

alternative strategy involving a Peterson oleﬁnation could arrive

at the same target 26. Anions derived from allyl trimethylsilanes

can attack a carbonyl electrophile through either α-position or

γ-position.¹⁵Using conditions developed by Magnus and co-

workers,¹⁶we observed exclusive formation of the vinylsilane

product 27 derived from reactivity in the γ position. A modiﬁed

Synthesis of the eastern subunit⁴and southern fragment are

shown in Scheme 5. Evans syn glycolate reaction between

oxazolidinone 36²²and readily available aldehyde 37⁸provided

the desired product in reasonable diastereoselectivity (7:1 dr)

17

procedure using MgBr₂failed to override this preference.

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and co-workers.^3aa,5The carboxylic acid 11 was available in four

straightforward steps from the commercially available ester 38.

With the subunits now constructed, our eﬀorts shifted toward

their combination. We were particularly focused on addressing

the diastereoselectivity in the methyl ketone aldol reaction

between 12 and 13. Prior to our entry into the ﬁeld, Pattenden^7e

and Kobayashi^7khad independently explored related coupling

strategies with limited success (Scheme 6). In both cases, poor

Scheme 4. Synthesis of Western Subunit

Scheme 6. Precedent for C₁₈−C₁₉Aldol Reaction

diastereoselectivity was observed (3:2 dr) as well as low

chemical yield (50% in Kobayashi’s case, no chemical yield

reported in Pattenden’s example). Stereocontrolling models for

β-silyloxy aldehydes such as 40 and 44 have been proposed;²³

however, it is unclear if the tertiary nature of the C₁₆silyl ether

is compatible with that analysis. In addition, models have

been developed for exploiting the stereochemical controlling

nature of α-chiral ketones (albeit primarily on ethyl ketone

substrates). We had hypothesized the poor stereocontrol in

these pioneering examples by Pattenden and Kobayashi could

be attributed to the absence of a chelating protecting group

at C₂₁, which rigidiﬁes the facial selectivity of the enolate in

the aldol transition state. Compelling evidence of the potential

for this strategy can be found in Chakraborty’s related

work toward amphidinolides G and H (which lack the C₁₆hy-

droxyl functionality).²⁴Pioneering precedent for the stereo-

controlling ability of α-oxy enolates had been reported by

Paterson,²⁵Heathcock,²⁶and Masamune;²⁷however, the majority

of the examples were on ethyl ketones. Aldol reactions using

methyl ketones have been reported to proceed through both chair

and boat transition states, which could lead to an erosion in

stereoinduction.²⁸White,²⁹Trost,³⁰and Evans³¹reported some of

the earliest successful examples in this area. Other laboratories

have subsequently explored this transformation with varying

degrees of stereocontrol.³²

Scheme 5. Synthesis of Eastern and Southern Subunits

Our exploration into the diastereoselective aldol reaction is

detailed in Scheme 7. We initially employed the unconjugated

diene 35 as a model for the actual system. To our considerable

disappointment, this substrate 35 performed poorly in the

transformation, providing low diastereoselectivity (2:1 dr) in

modest chemical yield (60%) (eq 1). Similar results were observed

with the achiral aldehyde 3,3-dimethylbutanal (2−3:1 dr) (eq 2).

and good yield. After TES silylation, subsequent conversion to

the thioester with lithium thiolate followed by cuprate addition

yielded the methyl ketone 13. This strategy for synthesis of the

C₁₉−C₂₆subunit has been subsequently exploited by Furstner

̈

D

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Scheme 7. Methyl Ketone Aldol Reaction

Scheme 8. Unsuccessful Macrocyclization Strategy

Undeterred by these discouraging model studies, we next studied

the conjugated diene system 12 (eq 3). We were delighted to see

that this transformation proceeded with high levels of stereo-

control; we only observed a single diastereomer in 69% yield. The

conﬁguration of the newly established stereocenter was conﬁrmed

by advanced Mosher ester method.³³The subtle nature of the

controlling inﬂuences of this aldol reaction warrants further

comment. We are hesitant to put forth a model for the controlling

inﬂuences of this transformation; however, it is important to note

that both the trisubstituted alkene at C₁₄−C₁₅and the chelating

protecting group at C₂₁appear to work in concert to inﬂuence the

stereochemical outcome of the aldol reaction. The C₁₆silyl ether

does not appear to exert considerable inﬂuence as this chelation

strategy has subsequently proven useful in amphidinolide G/H

Based on our frustrations with facilitating a successful

Mitsunobu macrolactonization, we decided a reorganization of

our strategy for macrocyclic formation was needed. Speciﬁcally,

we turned to inverting the C₂₅stereocenter prior to coupling,

forming the C₁ester bond in an intermolecular fashion and

constructing the C₈−C₉alkene through an intramolecular

pathway. Toward this end, synthesis of a modiﬁed methyl

ketone 54 was necessary (Scheme 9). Selective TES removal

could be accomplished under aqueous acidic conditions in

excellent yield. Martin’s modiﬁed Mitsunobu conditions

proceeded smoothly to give the inverted C₂₅ester. Finally,

saponiﬁcation of the PNB moiety with Ba(OH)₂·8H₂O and

methanol followed by TMS protection revealed the coupling

partner 54.

Synthesis of the modiﬁed aldehyde coupling partner is

illustrated in Scheme 10. Conversion of the C₉nitrile to its

corresponding acetate was accomplished via DIBAL-H reduction

to the aldehyde followed by NaBH₄reduction to the alcohol and

acylation. Regioselective functionalization at C₁₈was again

accomplished using Sharpless AD conditions followed by

periodate cleavage to reveal the C₁₈aldehyde.

series by both Furstner^3aa,5and Zhao³⁴which does not contain the

̈

C₁₆alcohol moiety.

The construction of the macrocyclization precursor is shown

in Scheme 8. Silylation of the C₁₈alcohol proceeded smoothly

with TBSOTf and a large excess of triethylamine.³⁵Interestingly,

use of near stoichiometric amounts of an amine base [e.g.,

2,6-lutidine (1.2 equiv)] led to elimination (∼20%) and alkene

isomerization (∼10%). Regioselective reduction of the C₉nitrile

was accomplished with DIBAL-H. Horner-Wadsworth-Emmons

36

oleﬁnation of the resultant aldehyde using Ba(OH)₂yielded

the desired α,β-unsaturated ketone in good yield and excellent

E/Z selectivity. Alternate conditions on related systems (DBU,

LiCl or KHMDS, THF) were less eﬀective for this oleﬁnation.³⁷

Subsequent selective cleavage of the C₂₅TES ether produced the

key Mitsunobu macrolactonization¹²precursor. Unfortunately,

this substrate was resistant to all eﬀorts to facilitate the macrocycle

formation under these sterochemically invertive conditions.

While the original route to the aldehydes 12 and 57 was

eﬀective, it suﬀered from logistical impracticalities; notably, the

titanium-mediated coupling of the allyl silane proved to be a

scale-dependent reaction and the thionyl chloride elimination

step gave a mixture of oleﬁn products. Consequently, we sought

to develop a more scalable approach to this subunit (Scheme 11).

E

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Scheme 9. Second-Generation Synthesis of Eastern Subunit

Scheme 11. Second Generation Approach to the C₉−C₁₈

Western Fragment of Amphidinolide B₁

Scheme 10. Modiﬁcation of the Western Subunit

Starting from the commercially available Oppolzer sultam

derivative 59, cuprate addition in accord with conditions

developed by Paquette³⁸cleanly generated the key C₁₁stereo-

center in compound 60. After functional group manipulation to

provide aldehyde 61, we were gratiﬁed to ﬁnd that key sequential

Wittig/Horner−Wadsworth−Emmons (HWE) reactions cleanly

introduced the triene 63 as a single stereoisomer. After DIBAL-H

reduction, the resulting trienyl alcohol proved remarkably reactive

to Sharpless asymmetric epoxidation conditions (proceeding at

−78 °C to −50 °C) to provide epoxide 64. In fact, if this reaction

was performed at higher temperatures (e.g., −20 °C), another

product was observed that appeared to be the result of a 1,2-alkyl

shift to produce an aldehyde.³⁹Subsequent Red-Al reduction

provided the diol 65. Finally, protecting group exchange followed

by 1° TES deprotection and oxidation provided the C₉−C₁₈

subunit 57. The high eﬃciency of this route (11.5% overall yield)

provided us with access to gram quantities of aldehyde 57.

With these modiﬁed coupling partners in hand, we revisited

our aldol coupling strategy (Scheme 12). We were pleased to

observe that similar levels of diastereoselectivity continued to

be observed using the LDA conditions (62% yield, >20:1 dr).

Silylation of the C₁₈alcohol proved signiﬁcantly more

complicated than expected. Use of TBSOTf led to signiﬁcant

exchange of the C₂₅TMS ether to the corresponding TBS ether.

Use of TESOTf minimized this problem, providing a 95% yield

of a 5:1 ratio of the C₂₅TMS to C₂₅TES. Both of these

compounds were productive intermediates and could be

converted to the corresponding C₂₅alcohol using HOAc/

THF/H₂O conditions. Intermolecular Yamaguchi esteriﬁcation

provided the phosphonate 71. Next, removal of the C₉acetate

was cleanly accomplished using Ba(OH)₂•8H₂O. Subsequent

oxidation using TPAP provided the aldehyde cyclization pre-

cursor 73. Interestingly, this compound proved to be surprisingly

reactive−leading to spontaneous macrocyclization under the

TPAP conditions. Ba(OH)₂·8H₂O was added to drive this

transformation to completion with an 85% overall yield from the

alcohol 72.

With the macrocycle in hand, the remaining challenges to be

addressed were the successful incorporation of the C₆−C₉allylic

epoxide and global deprotection (Scheme 13). CBS reduction⁴⁰

proceeded smoothly to provide the desired allylic alcohol 75 in

excellent diastereoselectivity. Subsequent Sharpless asymmetric

epoxidation⁴¹provided the desired epoxide 76 in 10:1 dr.

Incorporation of the alkene could be best accomplished by

inversion at C₇to provide the selenide 78⁴²followed by TPAP

F

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Scheme 12. Spontaneous Macrocyclization Strategy

mediated oxidation⁴³to the selenoxide and syn elimination to

yield the allylic epoxide as a single oleﬁn geometry. Despite

compelling precedent from Nicolaou and co-workers for a

related deprotection in the synthesis of amphidinolide N,^2vwe

were unable to eﬀect PMB removal using DDQ under buﬀered

aqueous or anhydrous conditions. Based on this unfortunate

result, it became clear that an alternate C₂₁protecting group

strategy was necessary to complete the total synthesis of

amphidinolide B₁.

Scheme 13. Incorporation of the Allylic Epoxide Moiety

We initially considered a 3,4-dimethoxybenzyl (DMB)

protecting group as a viable alternative to the C₂₁PMB group

as DMB groups are more readily oxidized by DDQ (Scheme 14).

We synthesized the necessary C₁₉−C₂₆subunit via an analogous

route as described previously. Interestingly, aldol reaction with

the C₁₈aldehyde 82 proceeded smoothly but in signiﬁcantly

lower diastereoselectivity (4:1 dr). We are unsure as to the cause

of this diﬀerence between the PMB and DMB series. Next, we

explored the possibility of deprotecting the C₂₁DMB group

using DDQ. Interestingly, treatment of 83 with DDQ under

buﬀer aqueous conditions led to formation of the acetal 86 in

modest yield, but as a single diastereomer. This product is likely

the result of initial oxidation to the oxonium ion followed by

nucleophilic attack by the C₂₂OTES ether. Subsequent silyl

migration to the C₁₈position would produce the observed

product 86. Despite this encouraging early result, we were unable

to increase the chemical yield of this transformation through

variation of oxidant or reaction conditions. Consequently, this

approach was abandoned.

Given our setbacks with benzyl-derived protection at C₂₁, we

revisited our central strategy for stereocontrol at C₁₈through the

C₂₁chelation model described previously (Scheme 15).

Traditionally, silyl protecting groups are not viewed as moieties

that participate in chelation;⁴⁴however, it is important to

acknowledge work by Heathcock,⁴⁵Eliel and Frye,⁴⁶Willard⁴⁷

and Evans⁴⁸which showed that silyl chelation is feasible under

certain conditions. We were particularly drawn to Heathcock’s

work in the area in which TMEDA was a key additive in their

chelation-controlled aldol reaction (eq 1). Alternatively, a dipole

minimization stereocontrol model produced the alternate facial

attack on the aldehyde (eq 2). Silyl protection at C₂₁would

G

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Scheme 14. C₂₁Dimethoxybenzyl Protection Series

Scheme 16. Tris-silyl Methyl Ketone Synthesis

Scheme 15. Heathcock’s Pioneering Stereoselective Aldol

Work

Scheme 17. Exploration into Aldol Stereoselectivity

simplify the endgame deprotection sequence and circumvent the

problematic DDQ deprotection strategy.

The synthesis of the C₂₁silyl methyl ketone 98 is shown in

Scheme 16. One attractive advantage to this strategy is that it

greatly simpliﬁes the synthesis of the methyl ketone as diﬀerential

protection at C₂₁and C₂₂is no longer needed. Oleﬁnation of

aldehyde 37 provided the α,β-unsaturated enone 93. Sharpless

dihydroxylation under buﬀered conditions yielded the diol in

good diastereoselectivity. Bis-silyl protection using TESOTf

cleanly provided the tris-TES methyl ketone 95. The C₂₅TES

ether could be cleanly removed using HOAc/THF/H₂O conditions

followed by inversion and protection as its C₂₅TMS ether.

Exploration of the key aldol reaction on the C₂₁silyl series

generated intriguing results (Scheme 17 and Table 1). Initial

studies with the C₂₅epimer 95 exhibited poor diastereoselectivity,

but good reactivity under the Heathcock’s TMEDA conditions

(entry 1). It should be noted that the replacement of THF with

Table 1. Exploration into Aldol Stereoselectivity

entry

substrates

conditions

yield (%) [dr]

1

2

3

4

5

6

95, 82

98, 82

98, 57

THF, −78 °C

Et₂O, −78 °C

THF, −78 °C

THF, −40 °C

THF, −100 °C

THF, −40 °C

64 [1.1:1 (99:102)]

<10 [1.5:1 (99:102)]

67 [1:5 (100:103)]

68 [1.8:1 (100:103)]

65 [1:8 (101:104)]

66 [1.2:1 (101:104)]

Et₂O led to a dramatic decrease in chemical yield (entry 2).

Interestingly, use of the required C₂₅stereochemistry for

amphidinolide B led to a more stereoselective aldol process

H

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(entries 3−6). If the reaction was conducted at −78 °C, the

transformation appeared to proceed through a dipole minimization

model to yield the 18R stereochemistry as the major product (5:1

103:100). If the otherwise identical transformation was conducted

at −40 °C, the stereoselectivity for the transforma-

tion reversed to now favor the 18S stereochemistry. This divergent

stereocontrol model could be attributed to reversible nature of

aldol reactions.⁴⁹A similar phenomenon was observed with the

aldehyde 57 (entries 5 and 6). While unexpected, these results

opened the door for the synthesis of both amphidinolide B₁and B₂.

Synthesis of the macrocycle using the aldol products was

accomplished based on close analogy to our C₂₁PMB series

(Scheme 18). TES protection at C₁₈using TESCl/DMAP

Figure 2. ORTEP Representation of Macrocycle 109.

Scheme 18. Second-Generation Macrocycle Formation

were incorporation of the allylic epoxide moiety and global

deprotection. We ﬁrst advanced the 18S stereoisomer, which

would lead to the synthesis of amphidinolide B₂(Scheme 19).

CBS reduction produced the allylic alcohol in good diaster-

eoselectivity. Although epoxidation under tartrate-mediated

Sharpless conditions as used previously proved ineﬀective,

titanium-mediated epoxidation (in the absence of tartrate ligand)

produced the epoxide alcohols in modest diastereoselectivity

(2:1 dr, 74% yield). Given the increased steric demands of the

Ti−tartate complex, we attribute the reactivity diﬀerence between

the C₂₀OPMB series and the C₂₀OTES series to a conformational

change to the macrocycle, which increases the steric hindrance

surrounding the allylic alcohol moiety. While we cannot rigorously

assign the stereochemistry of the newly created stereocenters, they

were assigned based on literature precedent.^40,50Incorporation of

the selenide followed by TPAP-mediated oxidation and syn

elimination provided the allyl epoxide 116. Unfortuantely, we

were again unable to eﬀect global desilylation under a range of

conditions (e.g., TAS-F or HF·pyr). Fortunately, the ordering of

the ﬁnal events could be altered (global deprotection followed

by syn elimination using TMSOOTMS for selenide oxidation) to

reveal the proposed structure for amphidinolide B₂(3). It should

be noted that the use of TMSOOTMS has not been previously

reported for selenide oxidation/elimination. H₂O₂was ineﬀective

in this transformation, likely due to unwanted Baeyer−Villiger-

type oxidation of the C₂₀ketone. To our surprise, the spectral

data did not match the literature values for amphidinolide B₂.

We had presumed that the incorrect epoxide had been utilized.

Consequently, we repeated the analogous endgame, but this

product 114 also did not match the natural product. It became

clear that the assignment of amphidinolide B₂was incorrect.

Comparison of the synthesized material with the literature data

revealed a large chemical shift diﬀerence for H₁₄[isolation data:

5.93 (bs), synthetic 3: 6.06 (bs), synthetic 114: 6.08 (bs)] and

conditions followed by C₂₅desilylation revealed the C₂₅alcohol.

Yamaguchi esteriﬁcation followed by saponiﬁcation of the

acetate protecting group produced the C₉alcohol. As employed

in our previous macrocyclization, TPAP oxidation produced the

reactive aldehyde, which appeared to undergo spontaneous

macrocyclization. The cyclization could be driven to completion

by addition of Ba(OH)₂·8H₂O for 18S series and LiCl/Hunig’s

base for the 18R series for optimal yields. While the yields for

these macrocyclizations were not as high as the C₂₁PMB series,

the ability to successfully close the macrocycle was gratifying.

Fortuitously, macrocycle 109 produced crystals suitable for X-ray

crystallographic analysis, thereby conﬁrming the stereochemical

assignment (Figure 2).

H

_19a,b[isolation data: 3.09 (dd, J = 2.3, 8.8 Hz, 1H) and 2.69 (dd,

J = 8.6, 17.7 Hz, 1H), synthetic 3: 3.05 (m) and 2.48 (dd, J = 8.0,

17.0 Hz), synthetic 114: 2.90 (dd, J = 9.9, 17.1 Hz) and 2.45 (m)].

Careful inspection of the structure elucidation paper^2crevealed

that while amphidinolide B₁was assigned by crystallographic

analysis, amphidinolide B₂was assigned based on analogy and

comparison of the NMR spectra. We hypothesize that the actual

structure of amphidinolide B₂likely contains the opposite

stereochemistry at C₁₆(e.g., 117), thereby maintaining a syn

relationship between the two alcohols at C₁₆and C₁₈.

The successful completion of amphidinolide B₁is shown in

Scheme 20. Starting from the macrocycle 109, CBS reduction

provided the allylic alcohol 118 in 74% yield (3.5:1 dr).

Titanium-mediated epoxidation of the alkene was high yielding,

With the macrocycle in hand and the stereochemistry ﬁrmly

established, the remaining hurdles for completing the synthesis

I

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Scheme 19. Synthesis of Proposed Structure for Amphidinolide B₂

but unselective (1:1.5 dr). Incorporation of the aryl selenide

using previously described conditions followed by global

deprotection and selenide oxidation/syn elimination yielded

amphidinolide B₁(2). Comparison of the synthetic material

with literature values showed excellent agreement (¹H NMR,

¹³C NMR, [α]_D). For analogue studies, we also carried the epimeric

epoxide series onto 8,9-epi-amphidinolide B₁(121).

MOLT-4 ALL, Reh ALL, U266 myeloma, KG1a AML and

HL60 AML cells were seeded in 96-well plates (5000/well for

DU145 and MDA-MB-435, 10000/well for OCI-LY3, K562,

MOLT-4, Reh, U266, KG1a and HL60), incubated overnight at

37 °C in 5% (v/v) CO₂and exposed to 0.1 μM of compound 3

for 72 h. Absorbance was measured at 490 nm using an

automated ELISA plate reader. Each experiment was performed

in quadruplicate. Data are mean SD.

To assess the cytotoxic eﬀects of the proposed structure of

amphidinolide B₂on human solid and blood cancer cells, cell

viability assays were conducted using a nine cancer cell line

panel.⁵⁸Compound 3 diﬀerentially reduced cell viabilities at

0.1 μM in human DU145 prostate cancer, MDA-MB-435 breast

cancer, OCI-LY3 lymphoma, K562 CML, MOLT-4 ALL, Reh

ALL, U266 myeloma, KG1a AML and HL60 AML cells (Table 2).

To further understand these antitumor activities of amphidinolide

B₂, we determined IC₅₀values = 36.4 2.9 nM, 94.5 8.0 nM,

3.3 0.9 nM and 7.4 0.6 nM against DU145, MDA-MB-435,

KG1a and HL60 AML cancer cells, respectively (Table 3).

Next, compared the potency of compound 3 to C_8,9epimer

114 and C₁₈epimer 121 in DU145 prostate cancer cells, com-

pound 3 exhibited over 12-fold increase in biological activity

(Figure 3). These ﬁndings suggest that the stereochemistry

of the epoxide plays an important role in eliciting potent anti-

cancer eﬀects.

IC₅₀values of compound 3 were determined in human DU145

prostate cancer, MDA-MB-435 breast cancer, KG1a AML and

HL60 AML cells. Cells were seeded in 96-well plates (5000/well

for DU145 and MDA-MB-435, 10000/well for KG1a and

HL60), incubated overnight at 37 °C in 5% (v/v) CO₂and

exposed to compound 3 in a dose-dependent manner for 72 h.

Absorbance was measured at 490 nm using an automated ELISA

plate reader. Each experiment was performed in quadruplicate.

Data are mean SD.

CONCLUSION

■

In summary, the ﬁrst total synthesis of amphidinolide B₁and the

proposed structure for amphidinolide B₂has been achieved. In

our initial approach to this family, we utilized a chelation-

controlled aldol reaction to provide excellent stereoselectivity at

C₁₈. Unfortunately, late-stage removal of the PMB group proved

not feasible in our hands. Consequently, a revised approach

utilizing a dipole-minimized aldol provided access to a stereo-

selective aldol product. The stereoselectivity in this key aldol

Cell viability assays were carried out as described in the

Experimental Section. Human DU145 prostate cancer, MDA-

MB-435 breast cancer, OCI-LY3 lymphoma, K562 CML,

J

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Scheme 20. Synthesis of Amphidinolide B₁and 8,9-epi-

Amphidinolide B₁

Table 3. Determination of IC₅₀Values of Compound 3 against

Human Cancer Cells (nM)

DU145

HL60

KG1a

MDA-MB-435

94.5 8.0

36.4 2.9

7.4 0.6

3.3 0.9

Figure 3. Comparison of Synthetic Analogues for Biological Activity.

process could be controlled by variation of the temperature.

Other highlights of the synthetic route include two non-metal-

catalyzed methods to construct the C₁₃−C₁₅diene, a spontaneous

HWE macrocyclization strategy, and a novel late-stage epox-

idation/elimination strategy to incorporate the sensitive C₆−C₉

allylic epoxide moiety.

The proposed structure for amphidinolide B₂displays potent

and stereoselective antitumor activities against human solid and

blood tumor cells at low nanomolar concentrations that include

highly aggressive and metastatic prostate and breast cancer cells.

In contrast, C_8,9-epimer and C₁₈epimer exhibit an over 12-fold

decrease in antitumor activity in comparison. The stereochemistry

of the epoxide plays a key role in the anticancer eﬀects.

to the residually protonated solvent. HRMS data was collected using a

TOF mass spectrometer.

Routine monitoring of reactions was performed using EM Science

DC-Alufolien silica gel, aluminum-backed TLC plates. Flash chroma-

tography was performed with the indicated eluents on EM Science

Gedurian 230−400 mesh silica gel.

Air- and/or moisture-sensitive reactions were performed under usual

inert atmosphere conditions. Reactions requiring anhydrous conditions

were performed under a blanket of argon, in glassware dried in an oven

at 120 °C or by ﬂame, then cooled under argon. Dry THF and DCM

were obtained via a solvent puriﬁcation system. All other solvents and

commercially available reagents were either puriﬁed via literature

procedures or used without further puriﬁcation.

EXPERIMENTAL SECTION

■

General Methods. Infrared spectra were recorded neat unless

otherwise indicated and are reported in cm⁻¹. H NMR spectra were

1

recorded in deuterated solvents and are reported in ppm relative to

tetramethylsilane and referenced internally to the residually protonated

solvent. ¹³C NMR spectra were recorded in deuterated solvents and are

reported in ppm relative to tetramethylsilane and referenced internally

Lactone 20. To a solution of diisopropylamine (1.67 g, 2.3 mL,

16.5 mmol) in THF (7.6 mL) at −78 °C was added n-BuLi (6.6 mL,

Table 2. Eﬀects of Compound 3 on Viabilities of Human Cancer Cells (% control)

DU145

31

MDA-MB-435

54 10

OCI-LY3

0

K562

67

MOLT-4

47

Reh

82

U266

76

KG1a

10

HL60

0

5

6

4

5

2

K

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16.5 mmol, 2.5 M in hexanes) dropwise. After 10 min, the white slurry

was warmed to −10 °C for 30 min. Then, the solution was cooled to

−78 °C, and another 58 mL of THF was added slowly to the above

solution. Next, a solution of Seebach lactone 18⁵¹(2.37 g, 15.0 mmol) in

THF (15 mL) was added dropwise to the above solution. After 20 min, a

solution of cinnamyl bromide 19 (4.43 g, 3.33 mL, 22.5 mmol) in THF

(10 mL) was added dropwise. After 30 min, the reaction was warmed

slowly to −10 °C over 2 h. After 5 min, the reaction was quenched with

satd aq NH₄Cl (30 mL) and warmed to rt. After 10 min, the organic

layer was separated, and the aqueous layer was extracted with Et₂O

(3 × 30 mL). The dried (MgSO₄) extract was concentrated in vacuo and

puriﬁed by chromatography over silica gel, eluting with 2−10% EtOAc/

hexanes, to give 20 (3.74 g, 13.7 mmol, 91%) as a white solid:

7.20−7.35 (m, 5H), 4.66−4.69 (m, 1H), 4.69 (s, 1H), 4.64 (s, 1H),

4.14−4.19 (m, 2H), 4.06 (q, J = 6.9 Hz, 1H), 3.26 (dd, J = 3.3, 13.2 Hz,

1H), 2.71 (dd, J = 3.9, 13.2 Hz, 1H), 2.52 (dd, J = 7.5, 14.4 Hz, 1H), 2.04

(dd, J = 7.5, 14.4 Hz, 1H), 1.59 (d, J = 3.6 Hz, 2H), 1.17 (d, J = 6.9 Hz),

0.04 (s. 9H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 153.5, 145.1, 135.8,

129.9, 129.3, 127.7, 109.7, 66.3, 55.7, 42.6, 38.4, 36.2, 26.8, 17.4, −1.0;

HRMS (FAB+) calcd for C₂₀H₃₀NO₃Si (M + H) 360.1995, found

360.1989.

[α]²³+45.5 (c 1.21, CHCl₃); IR (thin ﬁlm) 3027, 2963, 1796, 1484,

D

1173, 1138, 970, 692 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.28−7.42

(m, 5H), 6.58 (d, J = 15.6 Hz, 1H), 6.23 (dt, J = 15.6, 6.0 Hz, 1H), 5.24

(s, 1H), 2.72 (dd, J = 6.0, 10.8 Hz, 1H), 2.62 (dd, J = 6.0, 10.8 Hz, 1H),

1.51 (s, 3H), 0.98 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 175.5, 137.1,

135.3, 128.8, 127.9, 126.5, 122.4, 108.9, 80.2, 40.3, 34.8, 23.5, 23.1;

HRMS (FAB+) calcd for C₁₇H₂₃O₃(M + H) 275.1647, found 275.1650.

Allylsilane 24. To a solution of 23 (1.88 g, 5.23 mmol) in THF

(35 mL) at 0 °C were added sequentially MeOH (0.20 g, 0.25 mL,

6.28 mmol) followed by LiBH₄(3.14 mL, 6.28 mmol, 2.0 M in THF).

After 2 h at 0 °C, the reaction was warmed to rt. After 2 h, the reaction

was quenched with satd aq sodium tartrate (25 mL). After stirring for

20 min, the organic layer was separated, and the aqueous layer was

extracted with Et₂O (3 × 25 mL). The dried (MgSO₄) extract was

concentrated in vacuo and puriﬁed by chromatography over silica gel,

eluting with 15−25% Et₂O/pentane, to give free alcohol SI-1 (0.96 g,

5.18 mmol, 99%) as a colorless oil: [α]²³_D(+) 9.4 (c 0.84, CHCl₃); IR

(thin ﬁlm) 3337 (br), 3072, 2954, 2916, 1631, 1455, 1419, 1248, 1036,

Methyl Ketone 16. To a solution of lactone acetal 20 (1.37 g,

5.0 mmol) in THF (100 mL) at −78 °C was added MeLi (4.64 mL,

5.6 mmol, 1.2 M in Et₂O) via syringe pump. After 15 min, the resulting

solution was warmed to rt. After an additional 10 min, the solvent was

concentrated in vacuo, diluted with Et₂O (50 mL), ﬁltrated through a

plug of Celite, and concentrated again in vacuo. The yellow oil was

puriﬁed by chromatography over silica gel, eluting with 10−30%

EtOAc/hexanes, to give a ketone intermediate (0.78 g, 3.85 mmol, 77%)

as a colorless oil. To a solution of the above intermediate (340 mg,

1.66 mmol) in THF (8.3 mL) at −78 °C was added 2,6-lutidine (0.27 g,

0.29 mL, 2.49 mmol). After 5 min, TESOTf (0.53 g, 0.45 mL,

1.99 mmol) was added. After 30 min, the reaction was warmed to rt.

After 5 min, the reaction was quenched with satd aq NH₄Cl (10 mL).

After 10 min, the organic layer was separated, and the aqueous layer was

extracted with Et₂O (3 × 15 mL). The dried (MgSO₄) extract was

concentrated in vacuo and puriﬁed by chromatography over silica gel,

eluting with 2−6% EtOAc/hexanes, to give 16 (448 mg, 1.41 mmol,

88%) as a colorless oil: [α]²³_D+0.7 (c 0.70, CHCl₃); IR (thin ﬁlm) 3027,

2955, 2916, 2876, 1718, 1457, 1415, 1350, 1239, 1166, 1131, 1016, 742

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.20−7.33 (m, 5H), 6.38 (d, J =

15.9 Hz, 1H), 6.09−6.20 (m, 1H), 2.40−2.63 (m, 2H), 2.21 (s, 3H),

1.38 (s, 3H), 1.01 (t, J = 7.5 Hz, 9H), 0.68 (q, J = 7.5 Hz, 6H); ¹³C NMR

(100 MHz, CDCl₃) δ 214.2, 137.8, 133.6, 128.9, 127.6, 126.5, 125.1,

83.0, 45.2, 26.2, 25.4, 7.6, 7.1; HRMS (FAB+) calcd for C₁₉H₃₁O₂Si

(M + H) 319.2093, found 319.2094.

1

849 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 5,60 (d, J = 15.6 Hz, 2H),

3.44−3.52 (m, 2H), 2.03−2.10 (m, 1H), 1.77−1.89 (m, 2H), 1.54

(s, 2H), 1.41 (t, OH), 0.91 (d, J = 6.3 Hz, 3H), 0.04 (s, 9H); ¹³C NMR

(75 MHz, CDCl₃) δ 146.6, 109.2, 68.7, 43.1, 34.2, 26.7, 17.2, −0.9;

HRMS (FAB+) calcd for C₁₀H₂₂OSi (M) 186.1440, found 186.1447.

TIPS Ether 24. To a solution of alcohol intermediate SI-1 (308 mg,

1.65 mmol) in CH₂Cl₂at −78 °C were added sequentially Et₃N (0.25 g,

0.34 mL, 2.48 mmol) and TIPSOTf (607 mg, 0.53 mL, 1.98 mmol).

After 20 min, the reaction was warmed to rt. After 5 min, the reaction was

quenched with satd aq NH₄Cl (25 mL). After 5 min, the organic layer

was separated, and the aqueous layer was extracted with Et₂O (3 × 20 mL).

The dried (MgSO₄) extract was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 1% EtOAc/hexanes, to give 24

(560 mg, 1.64 mmol, 99%) as a colorless oil: [α]²³_D−4.9 (c 0.98, CHCl₃);

IR (thin ﬁlm) 3072, 2944, 2866, 1631, 1463, 1387, 1248, 1103, 1068, 878,

849, 796, 681 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 4.57−4.58 (m, 1H),

4.54 (s, 1H), 3.47−3.51 (m, 2H), 2.18 (dd, J = 5.4, 13.8, 1H), 1.78−1.82 (m,

1H), 1.63−1.71 (m, 1H), 1.51 (s, 2H), 1.04−1.08 (m, 21H), 0.87 (d, J = 6.6

Hz, 3H), 0.20 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 146.6, 108.8, 68.9,

42.7, 34.6, 26.7, 18.5, 17.0, 12.4, −0.9; HRMS (FAB+) calcd for C₁₉H₄₂OSi₂

(M⁺) 342.2774, found 342.2772.

Allylsilane 23. To a solution of NaHMDS (5.6 mL, 5.6 mmol, 1.0 M

in THF) at −78 °C was added a solution of imide 21 (1.09 g, 4.67

mmol) in THF (4.6 mL). After 20 min, a solution of allyl iodide 22⁵²

(3.6 g, 14 mmol) in THF (3 mL) was added via cannula. After 10 min,

the reaction was warmed slowly to 10 °C over 4 h and quenched with

satd aq NH₄Cl (25 mL). After 10 min at rt, the organic layer was

separated and the aqueous layer was extracted with Et₂O (3 × 20 mL).

The dried (MgSO₄) extract was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 4−15% EtOAc/hexanes,

Tertiary Alcohol 28. To a solution of allylsilane 24 (214 mg,

0.62 mmol) and ketone 16 (96 mg, 0.3 mmol) in CH₂Cl₂(3.0 mL) at

−78 °C was added freshly distilled TiCl₄(117.6 mg, 70 μL, 0.62 mmol)

via microsyringe dropwise. After 15 min, the dark red solution was

quenched with satd aq K₂CO₃(5 mL) and warmed to rt immediately.

After 20 min, the organic layer was separated and the aqueous layer

was extracted with Et₂O (3 × 20 mL). The dried (MgSO₄) extract was

concentrated in vacuo and puriﬁed by chromatography over silica gel,

eluting carefully with 0.5−2% EtOAc/hexanes, to give 28 (382 mg,

to give 23 (1.46 g, 4.06 mmol, 87%) as a colorless oil: [α]²³+30.6

D

(c 0.66, CHCl₃); IR (thin ﬁlm) 2954, 1780, 1699, 1632, 1454, 1385,

1349, 1246, 1207, 1101, 851, 701 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ

L

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0.19 mmol, 65%) as a colorless oil of a mixture of isomers (dr = 6:1).

Major isomer: H NMR (300 MHz, CDCl₃) δ 7.24−7.39 (m, 5H),

eluting with 20% EtOAc/hexanes, to give diol 30 (20 mg, 0.069 mmol,

61%) as a white foam: [α]²³_D−4.9 (c 0.98, CHCl₃); IR (thin ﬁlm) 3373

(br), 3026, 2955, 2925, 2870, 1722, 1627, 1448, 1373, 1032, 966, 897,

741, 692 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.23−7.38 (m, 5H), 6.46

(d, J = 15.6 Hz, 1H), 6.12−6.20 (m, 1H), 5.97 (s, 1H), 5.07 (s, 1H), 4.86

(s, 1H), 3.28−3.40 (m, 2H), 2.66 (dd, J = 7.2, 14.0 Hz, 1H), 2.46 (dd, J =

8.0, 14.0 Hz, 1H), 2.26 (dd, J = 5.6, 13.6 Hz, 1H), 1.89 (s, 3H), 1.84−

1.88 (m, 1H), 1.61−1.66 (m, 1H), 1.42 (s, 3H), 0.85 (d, J = 6.8 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃) δ 145.0, 142.9, 137.7, 133.8, 129.0, 127.8,

126.5, 125.9, 125.1, 115.2, 76.0, 68.5, 44.4, 42.5, 34.9, 28.1, 16.6, 15.4;

HRMS (ES+) calcd for C₂₀H₂₈O₂Na (M + Na) 323.1987, found

323.1996.

1

6.35−6.44 (m, 2H), 4.93 (s, 1H), 4.84 (s, 1H), 3.57−3.61 (m, 1H),

3.43−3.48 (m, 1H), 2.55−2.60 (m, 2H), 2.35−2.40 (m, 1H), 2.31 (dd,

J = 5.7, 10.8, 1H), 2.16 (d, J = 9.9 Hz, 1H), 2.03 (dd, J = 5.7, 10.8 Hz,

1H), 1.85−1.88 (m, 1H), 1.33 (s, 3H), 1.20 (s, 3H), 1.08−1.10 (m,

21H), 0.99 (t, J = 6.0 Hz, 9H), 0.94 (d, J = 5.1 Hz, 3 H), 0.70 (q, J = 6.0

Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 146.1, 138.0, 132.5, 128.9,

127.9, 127.4, 126.4, 115.4, 81.9, 77.7, 68.6, 43.3, 42.2, 42.1, 34.8, 23.1,

21.3, 18.5, 17.5, 12.4, 7.7, 7.4; HRMS (FAB+) calcd for C₃₅H₆₄O₃Si₂

(M⁺) 588.4394, found 588.4382.

Diol 31: colorless oil; [α]²³+7.6 (c 1.21, CHCl₃); IR (thin ﬁlm)

D

3373, 3081, 3026, 2957, 2926, 2870, 1724, 1644, 1496, 1449, 1373,

1112, 1034, 967, 900, 739, 692 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ

7.23−7.39 (m, 5H), 6.49 (d, J = 15.6 Hz, 1H), 6.16−6.23 (m, 1H), 5.23

(s, 1H), 4.96 (s, 3H), 3.48−3.52 (m, 2H), 2.85−2.96 (m, 2H), 2.62−

2.66 (m, 1H), 2.48−2.52 (m, 1H), 2.18−2.24 (m, 1H), 1.86−1.93 (m,

2H), 1.40 (s, 3H), 0.94 (d, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 151.9, 146.9, 137.7, 134.3, 128.9, 127.7, 126.6, 125.7, 114.3,

111.8, 75.7, 68.6, 45.0, 40.1, 39.2, 34.3, 28.2, 17.1; HRMS (ES+) calcd

for C₂₀H₂₈O₂Na (M + Na) 323.1987, found 323.1989.

Dienes 26 and 29. To a solution of 28 (118 mg, 0.20 mmol) in

PhMe (5.0 mL) at −78 °C were added sequentially pyridine (79.0 mg,

0.08 mL, 1.0 mmol) and SOCl₂(71.4 mg, 44 μL, 0.60 mmol) via micro-

syringe. After 30 min, the reaction was quenched with satd aq NaHCO₃

(10 mL) and warmed to rt. After 20 min, the organic layer was separated,

and the aqueous layer was extracted with Et₂O (3 × 20 mL). The dried

(MgSO₄) extract was concentrated in vacuo and puriﬁed by chromato-

graphy over silica gel, eluting carefully with 0.5−1% EtOAc/hexanes,

to give a mixture of 26 and 29 (114 mg, 0.20 mmol, 99%, 2.2:1 ratio)

separable by HPLC as a colorless oil. Conjugate diene 26: [α]²³_D−43.2

(c 0.1, CHCl₃); IR (thin ﬁlm) 2954, 2866, 1640, 1459, 1156, 1119, 1013,

882, 741 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.20−7.34 (m, 5H), 6.35

(d, J = 12.0 Hz, 1H), 6.18 (dt, J = 12.0, 5.4 Hz, 1H), 5.89 (s, 1H), 5.01

(s, 1H), 4.82 (s, 1H), 3.44 (d, J = 4.2 Hz, 2H), 2.48−2.50 (m, 2H), 2.35

(dd, J = 3.6, 9.9 Hz, 1H), 1.84 (d, J = 0.9 Hz, 3H), 1.82 (dd, J = 3.6, 9.9

Hz, 1H), 1.66−1.72 (m, 1H), 1.46 (s, 3H), 1.07−1.09 (m, 21H), 1.00

(t, J = 5.7 Hz, 9H), 0.78 (d, J = 5.6 Hz, 3H), 0.64 (q, J = 5.7 Hz, 6H);

¹³C NMR (75 MHz, CDCl₃) δ 145.7, 142.8, 138.3, 131.9, 128.8, 127.4,

127.2, 126.3, 125.5, 114.5, 78.7, 68.6, 46.3, 42.6, 34.9, 27.2, 18.5, 16.7,

15.0, 12.4, 7.6, 7.2; HRMS (FAB+) calcd for C₃₅H₆₂O₂Si₂(M⁺)

570.4288, found 570.4277.

Nitrile 14. To a solution of 30 (98 mg, 0.33 mmol) in Et₂O (1.6 mL)

at 0 °C were added sequentially PPh₃(342 mg, 1.3 mmol) and DEAD

(0.24 mL, 1.3 mmol, 40% w/w in PhMe). After 15 min, acetone

cyanohydrin (70.0 mg, 74.5 μL, 0.82 mmol) was added dropwise. After

5 min, the reaction was warmed to rt. After 6 h, the reaction was con-

centrated in vacuo and puriﬁed by chromatography over silica gel,

eluting with 10% EtOAc/hexanes, to give a corresponding nitrile

intermediate (80 mg, 0.26 mmol, 81%) as a colorless oil: [α]²³+7.8

D

(c 0.99, CHCl₃); IR (neat) 3479 (br), 2962, 2927, 2246, 1733, 1496,

1456, 1420, 1381, 1105, 968, 902, 743, 694 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 7.26−7.37 (m, 5H), 6.47 (d, J = 16.0 Hz, 1H), 6.12−6.18 (m,

1H), 5.95 (s, 1H), 5.12 (s, 1H), 4.92 (s, 1H), 2.66 (dd, J = 7.2, 14.0 Hz,

1H), 2.48 (dd, J = 7.2, 14.0 Hz, 1H), 2.05−2.20 (m, 4H), 1.88 (s, 3H),

1.76−1.88 (m, 1H), 1.75 (br, 1H), 1.43 (s, 3H), 0.97 (d, J = 6.6 Hz, 3H);

¹³C NMR (75 MHz, CDCl₃) δ 143.8, 143.5, 137.5, 134.0, 129.0, 127.9,

126.5, 125.5, 124.3, 119.1, 116.4, 76.0, 44.8, 44.5, 29.3, 28.1, 24.2, 19.5,

15.5; HRMS (FAB+) calcd for C₂₁H₂₈NO (M + 1) 310.2171, found

310.2144.

Unconjugated diene 29: [α]²³−1.3 (c 1.74, CHCl₃); IR (thin

D

ﬁlm) 3026, 2942, 2865, 1643, 1495, 1462, 1381, 1241, 1097, 1012, 882

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.22−7.36 (m, 5H), 6.38 (d, J =

12.0 Hz, 1H), 6.16−6.20 (m, 1H), 5.16 (s, 1H), 4.92 (s, 1H), 4.89 (s,

1H), 4.88 (s, 1H), 3.55−3.59 (m, 1H), 3.44−3.47 (m, 1H), 2.84 (s, 2H),

2.47−2.50 (m, 2H), 2.25 (dd, J = 3.6, 9.9 Hz, 1H), 1.74−1.85 (m, 2H),

1.43 (s, 3H), 1.08−1.10 (m, 21H), 1.00 (t, J = 6.0 Hz, 9H), 0.92 (d, J =

4.8 Hz, 3H), 0.64 (q, J = 6.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ

152.0, 146.7, 138.3, 132.2, 128.9, 127.5, 127.2, 126.4, 113.9, 111.1, 78.3,

68.8, 46.4, 39.8, 38.8, 34.6, 27.5, 18.5, 17.2, 12.4, 7.6, 7.3.

To a solution of the above intermediate (80 mg, 0.26 mmol) in

CH₂Cl₂(1.0 mL) at −78 °C was added 2,6-lutidine (111.0 mg, 0.12 mL,

1.04 mmol) followed by TESOTf (136.9 mg, 0.12 mL, 0.52 mmol).

After 30 min, the reaction was warmed to rt and quenched with satd aq

NH₄Cl (3 mL). After 5 min, the mixture was extracted with Et₂O (3 ×

10 mL). The dried (MgSO₄) extract was concentrated in vacuo and puriﬁed

by chromatography over silica gel, eluting with 1% EtOAc/hexanes, to

give nitrile 14 (80 mg, 0.19 mmol, 72%) as a colorless oil: [α]²³_D−37.6

(c 0.98, CHCl₃); IR (neat) 2957, 2933, 2876, 2240, 1733, 1496, 1457, 1420,

1381, 1160, 1122, 1016, 967, 902, 742, 693 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 7.21−7.33 (m, 5H), 6.33 (d, J = 11.7 Hz, 1H), 6.15−6.19

(m, 1H), 5.87 (s, 1H), 5.07 (s, 1H), 4.87 (s, 1H), 2.50 (d, J = 5.4 Hz, 2H),

2.15 (dd, J = 5.4, 9.9 Hz, 1H), 2.00−2.06 (m, 3H), 1.81 (s, 3H), 1.72−1.79

(m, 1H), 1.47 (s, 3H), 1.02 (t, J = 5.7 Hz, 9H), 0.85 (d, J = 5.1Hz, 3H), 0.67

(q, J = 5.1 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 143.9, 143.7, 138.1,

131.9, 129.0, 127.4, 127.3, 126.3, 124.6, 119.0, 116.0, 78.8, 46.0, 44.9, 29.3,

Diols 30 and 31. To a mixture of 26 and 29 (75 mg, 0.13 mmol)

in THF (0.1 mL) at 0 °C was added TBAF (0.6 mL, 1.0 M in THF).

After 10 min, the reaction was warmed to rt. After 1 h, the reaction was

quenched with satd aq NH₄Cl (3 mL). After 10 min, the mixture was

extracted with Et₂O (3 × 10 mL). The dried (MgSO₄) extract was

concentrated in vacuo and puriﬁed by chromatography over silica gel,

M

dx.doi.org/10.1021/jo3026077 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

27.6, 24.1, 19.4, 15.1, 7.64, 7.26; HRMS (FAB+) calcd for C₂₇H₄₂OSiN

(M + 1) 424.3036, found 424.3044.

(dd, J = 0.6, 6.9 Hz, 2H), 2.24−2.32 (m, 1H), 1.97−2.17 (m, 4H),

1.38 (s, 3H), 0.95−1.04 (m, 12H), 0.58−0.68 (m, 6H); ¹³C NMR (75

MHz, CDCl₃) δ 151.7, 144.9, 138.1, 132.3, 128.9, 127.4, 127.1, 126.4,

119.2, 115.8, 111.1, 78.2, 46.4, 42.3, 38.2, 28.9, 27.7, 24.3, 20.0,

7.6, 7.3.

Aldehyde 12. To a solution of 14 (75 mg, 0.18 mmol) in t-BuOH/

H₂O (3 mL, 1:1) were added MeSO₂NH₂(25.6 mg, 0.27 mmol) and

AD mix β*⁵³(250 mg). After 16 h, the reaction was quenched with satd

aq Na₂S₂O₃(3 mL). After 20 min, the mixture was extracted with EtOAc

(3 × 10 mL). The dried (MgSO₄) extract was concentrated in vacuo and

puriﬁed by chromatography over silica gel, eluting with 20% EtOAc/

hexanes, to give a mixture of diol isomers (73 mg, dr = 6:1, 0.16 mmol,

89%) as a colorless oil. The diol substrate was applied to the next step

without further puriﬁcation.

Aldehyde 35. To a solution of 33 (26 mg, 62 μmol) in t-BuOH/

H₂O (1 mL, 1:1) were added MeSO₂NH₂(8.8 mg, 93 μmol) and AD

mix β*⁵³(87 mg). After 16 h, the reaction was quenched with satd aq

Na₂S₂O₃(3 mL). After 20 min, the mixture was extracted with EtOAc

(3 × 10 mL). The dried (MgSO₄) extract was concentrated in vacuo and

puriﬁed by chromatography over silica gel, eluting with 20% EtOAc/

hexanes, to give a mixture of the diol isomers (25.5 mg, dr = 1.3:1, 56

μmol, 90%) as a colorless oil. The diol substrate was applied to the next

step without further puriﬁcation.

A solution of the mixture described above in THF/Et₂O (2.8 mL,

1:1) was added NaIO₄(304 mg, 1.42 mmol) and H₂O (1.4 mL). After

2 h, the reaction was quenched with satd aq NaCl (3 mL), and the

mixture was extracted with Et₂O (3 × 10 mL). The dried (MgSO₄)

extract was concentrated in vacuo to give aldehyde 12 (54 mg,

A solution of the mixture described above in THF/Et₂O (1.24 mL,

1:1) was added NaIO₄(120 mg, 0.56 mmol) and H₂O (0.62 mL). After

2 h, the reaction was quenched with satd aq NaCl (3 mL) and the

mixture was extracted with Et₂O (3 × 10 mL). The dried (MgSO₄)

extract was concentrated in vacuo to give aldehyde 35 (18.5 mg, 0.053

mmol, 95%) as a colorless oil: [α]²³_D−11.4 (c 1.57, CHCl₃); IR (neat)

2958, 2915, 2876, 2737, 2246, 1722, 1645, 1457, 1417, 1375, 1239,

0.15 mmol, 96%) as a colorless oil: [α]²³−12.6 (c 1.22, CHCl₃); IR

D

(neat) 3081, 2957, 2917, 2876, 2246, 1722, 1628, 1457, 1417, 1381,

1240, 1163, 1126, 1046, 1017, 904, 802, 743 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 9.66 (t, J = 3.2 Hz, 1H), 5.99 (s, 1H), 5.10 (s, 1H), 4.89

(s, 1H), 2.61 (dd, J = 3.2, 14.8 Hz, 1H), 2.47 (dd, J = 2.8, 14.8 Hz, 1H),

2.32 (dd, J = 5.2, 16.8 Hz, 1H), 2.15−2.25 (m, 2H), 2.08 (dd, J =

7.2, 13.6 Hz, 1H), 1.83−1.92 (m, 1H), 1.80 (s, 3H), 1.47 (s, 3H), 1.04

(d, J = 6.4 Hz, 3H), 0.96 (t, J = 8.0 Hz, 9H), 0.63 (q, J = 8.0 Hz, 6 H);

¹³C NMR (100 MHz, CDCl₃) δ 203.2, 143.2, 142.7, 125.2, 118.9, 116.8,

54.5, 44.8, 30.1, 29.6, 28.3, 24.3, 19.8, 15.2, 7.5, 7.2; HRMS (FAB+)

calcd for C₂₀H₃₆O₂SiN (M + 1) 350.2515, found 350.2508.

1

1165, 1123, 1045, 1005, 909, 743, 726 cm⁻¹; H NMR (300 MHz,

CDCl₃) δ 9.66 (t, J = 3.0 Hz, 1H), 5.28 (s, 1H), 4.95 (s, 1H), 4.94

(s, 1H), 4.90 (s, 1H), 2.76 (s, 2H), 2.20−2.62 (m, 5H), 2.02−2.06 (m,

2H), 1.46 (s, 3H), 1.08 (d, J = 6.3 Hz, 3H), 0.96 (t, J = 7.8 Hz, 9H),

0.63 (q, J = 7.8 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 203.3, 150.5,

144.3, 119.0, 116.2, 112.6, 54.5, 42.1, 38.4, 28.9, 28.5, 24.3, 24.0, 19.9,

7.5, 7.2.

Methyl Ketone 13. To a solution of imide 36²²(107 mg, 0.3 mmol)

in PhMe (0.7 mL) at −50 °C were added sequentially Et₃N (34.4 mg,

48.2 μL, 0.34 mmol) and Bu₂BOTf (86.0 mg, 80.0 μL, 0.32 mmol). After

1.5 h, a solution of aldehyde 37⁸(46 mg, 0.20 mmol) in PhMe

(0.25 mL) was transferred dropwise into the reaction via cannula. After

40 min, the reaction was warmed to −30 °C within 30 min. After 1 h, the

reaction was quenched with aq phosphate buﬀer solution (0.5 mL,

pH 7), MeOH (0.5 mL), and THF (0.5 mL). Next, the mixture was

warmed up to rt. A solution of H₂O₂(0.5 mL, 30% H₂O₂in H₂O) in

MeOH (0.5 mL) was added dropwise. After 1 h, the reaction mixture

was extracted with EtOAc (3 × 15 mL) and the combined organic

extract was diluted with an aqueous phosphate buﬀer solution (20 mL,

pH 7). The mixture was concentrated in vacuo and extracted again with

Et₂O (3 × 10 mL). The dried (MgSO₄) extract was concentrated in

vacuo and puriﬁed by chromatography over silica gel, eluting with 15−

20% EtOAc/hexanes, to give an aldol adduct SI-4 (83 mg, 0.14 mmol,

72%) as a colorless oil: [α]²³_D−3.9 (c 0.83, CHCl₃); IR (thin ﬁlm) 3490

(br), 2956, 2875, 1781, 1708, 1612, 1514, 1389, 1248, 1211, 1051, 1012,

744 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.25−7.39 (m, 7H), 6.92 (d,

J = 8.8 Hz, 2H), 5.36 (d, J = 2.0 Hz, 1H), 4.64−4.72 (m, 1H), 4.64 (d, J =

10.8 Hz, 1H), 4.49 (d, J = 10.8 Hz, 1H), 4.20−4.29 (m, 2H), 3.84−3.90

(m, 1H), 3.82 (s, 3H), 3.61−3.64 (m, 1H), 3.34 (dd, J = 2.8, 13.2 Hz,

1H), 2.78 (dd, J = 3.6, 13.5 Hz, 1 H), 2.31 (d, J = 10.0 Hz, 1H), 1.74−

1.81 (m, 1H), 1.56−1.62 (m, 1H), 1.40−1.48 (m, 1H), 1.15 (d, J = 5.6

Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.99 (t, J = 7.6 Hz, 9H), 0.62 (q, J = 7.6

Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 171.6, 160.0, 153.6, 135.6,

130.7, 129.8, 129.6, 129.4, 127.8, 114.3, 78.4, 76.6, 73.0, 67.4, 67.3, 56.2,

Nitrile 33. To a solution of 31 (30 mg, 0.10 mmol) in Et₂O (0.5 mL,

0.2 M) at 0 °C were added sequentially PPh₃(104 mg, 0.4 mmol) and

DEAD (72 μL, 0.4 mmol, 40% solution in PhMe). After 15 min, acetone

cyanohydrin (21.2 mg, 23.0 μL, 0.25 mmol) was added dropwise. After

5 min, the reaction was warmed to rt. After 6 h, the reaction was con-

centrated in vacuo and puriﬁed by chromatography over silica gel,

eluting with 10% EtOAc/hexanes, to give a corresponding nitrile inter-

mediate (25 mg, 0.08 mmol, 81%) as a colorless oil.

To a solution of the above nitrile (25 mg, 0.08 mmol) in CH₂Cl₂

(0.32 mL, 0.25 M) at −78 °C were added sequentially 2,6-lutidine

(34.3 mg, 37 μL, 0.32 mmol) and TESOTf (42.1 mg, 36 μL, 0.16 mmol).

After 30 min, the reaction was warmed to rt and quenched with satd aq

NH₄Cl (3 mL). After 5 min, the mixture was extracted with Et₂O (3 ×

10 mL). The dried (MgSO₄) extract was concentrated in vacuo and

puriﬁed by chromatography over silica gel, eluting with 1% EtOAc/

hexanes, to give 33 (26 mg, 62 μmol, 77%) as a colorless oil: [α]²³

D

−13.6 (c 0.28, CHCl₃); IR (neat) 2957, 2933, 2911, 2875, 2247, 1238,

1157, 1123, 1063, 1005, 967, 905, 742, 693 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 7.17−7.26 (m, 5H), 6.35 (d, J = 15.9 Hz, 1H), 6.08−6.19 (m,

1H), 5.14 (s, 1H), 4.93 (s, 2H), 4.71 (s, 1H), 2.75−2.85 (m, 2H), 2.46

N

dx.doi.org/10.1021/jo3026077 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

55.7, 43.1, 38.2, 34.6, 23.6, 16.2, 7.3, 5.3; HRMS (FAB+) calcd for

C₃₂H₄₈NO₇Si (M + 1) 586.3200, found 586.3202.

Carboxylic Acid 11. To a solution of 38 (320 mg, 0.35 mL,

2.50 mmol) in THF/H₂O (35 mL, 1:1) at rt were added K₂OsO₄·H₂O

(14 mg, 15 μmol) and NaIO₄(2.4 g, 11.25 mmol). After 3 h, the reaction

was quenched with satd aq Na₂S₂O₃(5 mL). After 20 min, the mixture

was extracted with Et₂O (3 × 10 mL). The dried (MgSO₄) extract

was concentrated in vacuo to give an aldehyde intermediate (247 mg,

1.90 mmol, 76%) as a colorless oil. The aldehyde intermediate SI-7 was

used directly in the next step without further puriﬁcation.

To a solution of the above aldehyde intermediate SI-7 (247 mg,

1.90 mmol) in CH₂Cl₂(5.4 mL) at rt was added Wittig reagent Ph₃P

C(Me)CO₂t-Bu (725 mg, 2.0 mmol). After 30 min, the reaction was

concentrated in vacuo and puriﬁed by chromatography over silica gel,

eluting with 5% EtOAc/hexanes, to give Wittig product SI-8 (377 mg,

1.56 mmol, 82%) as a colorless oil: IR (neat) 2977, 1739, 1704, 1652,

TES Ether SI-5. To a solution of the aldol adduct SI-4 (78 mg,

0.13 mmol) in CH₂Cl₂(0.3 mL) at 0 °C were added sequentially 2,6-

lutidine (27.8 mg, 29.8 μL, 0.26 mmol) and TESOTf (68.5 mg, 60.1 μL,

0.26 mmol). After 1 h, the reaction was warmed to rt and quenched with satd

aq NH₄Cl (3 mL). After 5 min, the mixture was extracted with Et₂O (3 ×

10 mL). The dried (MgSO₄) extract was concentrated in vacuo and puriﬁed

by chromatography over silica gel, eluting with 4−6% EtOAc/hexanes, to

give the corresponding protected alcohol SI-5 (84 mg, 0.12 mmol, 90%) as

1

1456, 1436, 1367, 1289, 1252, 1159, 1121, 1083, 852, 743 cm⁻¹; H

NMR (300 MHz, CDCl₃) δ 6.59 (dt, J = 1.2, 7.5 Hz, 1H), 3.65 (s, 3H),

2.32 (t, J = 7.5 Hz, 2H), 2.17 (q, J = 7.5 Hz, 2H), 1.71−1.83 (m, 5H),

1.47 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 174.1, 167.8, 139.9, 130.5,

80.5, 51.9, 33.9, 28.5, 28.3, 24.2, 12.8; HRMS (FAB+) calcd for

C₁₃H₂₃O₄(M + 1) 243.1596, found 243.1598.

a colorless oil: [α]²³−33.8 (c 1.9, CHCl₃); IR (thin ﬁlm) 2956, 2911,

D

2875, 1785. 1704, 1612, 1513, 1456, 1381, 1248, 1082, 1011, 739 cm⁻¹; ¹H

NMR (300 MHz, CDCl₃) δ 7.34−7.26 (m, 7H), 6.84 (d, J = 8.4 Hz, 2H),

5.25 (d, J = 6.0 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H), 4.52 (d, J = 11.7 Hz, 1H),

4.46−4.49 (m, 1H), 4.03−4.12 (m, 3H), 3.73−3.98 (m, 1H), 3.79−3.81

(m, 1H), 3.74 (s, 3H), 3.11 (dd, J = 3.0, 13.2 Hz, 1H), 2.40 (dd, J = 3.0, 13.5

Hz, 1H), 1.47−1.55(m, 2H), 1.09(d, J = 6.0Hz, 3H), 0.87−0.97 (m, 21H),

0.53−0.63 (m, 12H); ¹³C NMR (75 MHz, CDCl₃) δ 172.3, 159.9, 153.3,

135.8, 130.6, 130.3, 129.7, 129.4, 127.8, 114.0, 79.6, 77.8, 73.4, 67.6, 66.8,

56.4, 55.6, 44.7, 37.8, 33.9, 24.1, 15.2, 7.5, 7.4, 5.8, 5.4; HRMS (FAB+) calcd

for C₃₈H₆₀NO₇Si₂(M − 1) 698.3908, found 698.3890.

Phosphonate SI-9. To a solution of methyl diethylphosphonate

(318 mg, 0.3 mL, 2.09 mmol) in THF (10 mL) at −78 °C was added

n-BuLi (0.83 mL, 2.09 mmol, 2.5 M in hexane). After 20 min, this

resulted solution was transferred dropwise into a solution of the above

Wittig product SI-8 (202 mg, 0.83 mmol) in THF (4 mL) at −78 °C via

cannula. After 30 min, the reaction was quenched with satd aq NH₄Cl

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

(MgSO₄) extract was concentrated in vacuo and puriﬁed by chromato-

graphy over silica gel, eluting with 80% EtOAc/hexanes, to give phos-

phonate intermediate SI-9 (254 mg, 0.65 mmol, 78%) as a colorless oil:

IR (neat) 2978, 2932, 1701, 1652, 1392, 1366, 1254, 1162, 1024, 965,

794 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 6.58 (dt, J = 1.2, 7.5 Hz, 1H),

4.07−4.17 (m, 4H), 3.09 (s, 1H), 3.01 (s, 1H), 2.63 (t, J = 7.2 Hz, 2H),

2.13 (q, J = 7.5 Hz, 2H), 1.75 (s, 3H), 1.67−1.75 (m, 2H), 1.46 (s, 9H),

1.31 (t, J = 7.2 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 202.0, 167.8,

140.2, 130.4, 80.5, 63.0, 43.7, 42.0, 28.5, 28.1, 22.7, 16.7, 12.8; HRMS

(FAB+) calcd for C₁₇H₃₂O₆P (M + 1) 363.1937, found 363.1942.

Methyl Ketone 13. To a solution of EtSH (75 mg, 90.2 μL,

1.21 mmol) in THF (9.0 mL) at 0 °C was added n-BuLi (0.43 mL,

1.07 mmol, 2.5 M in hexane). After 20 min, a solution of the above inter-

mediate (500 mg, 0.714 mmol) in THF (3.0 mL) was transferred via

cannula dropwise. After 20 min, the reaction was quenched with satd aq

NH₄Cl (10 mL). After 5 min, the mixture was extracted with Et₂O (3 ×

20 mL). The dried (MgSO₄) extract was concentrated in vacuo and puriﬁed

by a plug of silica gel, eluting with 10% EtOAc/hexanes, to give the corre-

sponding thioester intermediate (375 mg, 0.68 mmol, 95%) as a colorless oil.

To a suspension of CuI (796 mg, 4.18 mmol) in Et₂O (9.0 mL) at

0 °C was added MeLi (5.2 mL, 8.36 mmol, 1.6 M in Et₂O). After 15 min,

the colorless solution was cooled to −50 °C, and a solution of the

above thioester intermediate (375 mg, 0.68 mmol) in Et₂O (2.4 mL)

was transferred into the reaction dropwise via cannula. After 2 h, the

reaction was quenched with satd aq NH₄Cl (10 mL) at −50 °C, warmed

to rt, and extracted with Et₂O (3 × 20 mL). The dried (MgSO₄) extract

was concentrated in vacuo and puriﬁed by chromatography over silica

gel, eluting with 2−4% EtOAc/hexanes, to give methyl ketone 13

Acid 11. To a solution of the above phosphonate SI-9 (102 mg,

0.28 mmol) in CH₂Cl₂(1.5 mL) at 0 °C was added TFA (1.15 g, 0.75 mL,

9.7 mmol). After 5 min, the reaction was warmed to rt. After 2 h, the

reaction was concentrated in vacuo and puriﬁed by chromatography

over silica gel, eluting with 4% MeOH/CH₂Cl₂, to give 11 (84.8 mg,

0.28 mmol, 99%) as a colorless oil: IR (neat) 3418, 2986, 2934, 1772,

1715, 1395, 1209, 1163, 1023, 973, 799, 698 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 6.86 (t, J = 7.5 Hz, 1H), 6.07 (br, 1H), 4.12−4.23 (m, 4H),

3.18 (s, 1H), 3.10 (s, 1H), 2.64 (t, J = 7.2 Hz, 2H), 2.22 (q, J = 7.5 Hz,

2H), 1.82 (s, 3H), 1.71−1.80 (m, 2H), 1.30 (t, J = 7.5 Hz, 6H); ¹³C

NMR (75 MHz, CDCl₃) δ 202.2, 170.5, 143.5, 128.5, 63.2, 43.6, 41.9,

28.2, 22.5, 16.7, 12.5; HRMS (FAB+) calcd for C₁₃H₂₄O₆P (M + 1)

307.1311, found 307.1322.

(326 mg, 0.60 mmol, 89%) as a colorless oil: [α]²³+31.0 (c 0.80,

D

CHCl₃); IR 2956, 2912, 2876, 1716, 1613, 1514, 1457, 1416, 1249, 1172,

1082, 1037, 1007, 820, 740 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J

= 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.40 (d, J = 11.4 Hz, 1H), 4.38 (d, J

= 11.4 Hz, 1H), 3.81 (s, 3H), 3.69−3.81 (m, 3H), 2.11 (s, 3H), 1.45−1.48

(m, 3H), 1.09 (d, J = 6.0 Hz, 3H), 0.85−0.97 (m, 21H), 0.53−0.61 (m,

12H); ¹³C NMR (100 MHz, CDCl₃) δ 211.5, 159.8, 130.1, 129.9, 114.1,

88.9, 73.1, 67.4, 55.7, 44.9, 33.5, 27.4, 23.9, 14.3, 7.4, 7.3, 5.7, 5.4; HRMS

(FAB+) calcd for C₂₉H₅₅O₅Si₂(M + 1) 539.3588, found 539.3559.

Alcohol 48. To a solution of 13 (73 mg, 0.14 mmol) in Et₂O

(0.7 mL) at −78 °C was added LDA⁵⁴(0.15 mL, 1.0 M in THF). After

20 min, a precooled (−78 °C) solution of aldehyde 12 (31.5 mg,

O

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0.09 mmol) in Et₂O (0.4 mL) was transferred in one portion via cannula

at −78 °C. After 20 min, the reaction was quenched with satd aq NH₄Cl

(3 mL), and the mixture was extracted with Et₂O (3 × 10 mL). The

dried (MgSO₄) extract was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 5% EtOAc/hexanes, to give

Acid 9. To a solution of 49 (11 mg, 11 μmol) in PhMe (0.25 mL) at

−78 °C was added DIBAL-H (13.2 μL, 13.2 μmol, 1.0 M in PhMe)

dropwise. After 10 min, another portion of DIBAL-H (6.0 μL, 6.0 μmol,

1.0 M in PhMe) was added. The reaction was quenched sequentially

with MeOH (0.5 mL), satd aq tartaric acid (0.1 mL), and H₂O (2 mL).

Next, the mixture was warmed to rt. After 1 h, the mixture was

extracted with Et₂O (3 × 10 mL), and the dried (MgSO₄) extract was

concentrated in vacuo to give the unstable aldehyde 10 as a colorless oil.

The aldehyde was applied immediately to the next step without further

puriﬁcation.

To a solution of 11 (4.0 mg, 0.012 mmol) in THF/H₂O (0.2 mL,

40:1) at rt was added Ba(OH)₂·8H₂O (7.6 mg, 0.024 mmol). After

30 min, a solution of the above aldehyde intermediate 10 in THF

(0.15 mL) was added dropwise via cannula. After 16 h, the reaction was

quenched with satd aq NH₄Cl (2 mL) and the mixture was extracted

with Et₂O (3 × 10 mL). The dried (MgSO₄) extract was concentrated in

vacuo was applied immediately to the next step without further

puriﬁcation.

48 (55 mg, 0.06 mmol, 69%) as a colorless oil: [α]²³+21.3 (c 0.60,

D

CHCl₃); IR (neat) 3496, 2955, 2911, 2876, 1715, 1614, 1515, 1457,

1418, 1379, 1249, 1086, 1036, 1008, 903, 807, 740 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 7.27 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.87

(s, 1H), 5.09 (s, 1H), 4.89 (s, 1H), 4.47 (d, J = 10.8 Hz, 1H), 4.33−4.36

(m, 2H), 3.80 (s, 3H), 3.76−3.80 (m, 3H), 3.61 (s, 1H), 2.95 (dd, J =

7.2, 18.0 Hz, 1H), 2.05−2.40 (m, 6H), 1.88−1.95 (m, 1H), 1.81 (s, 3H),

1.52 (s, 3H), 1.37−1.52 (m, 5H), 1.07 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.0

Hz, 3H), 0.83−0.98 (m, 30H), 0.51−0.67 (m, 18H); ¹³C NMR

(100 MHz, CDCl₃) δ 212.1, 159.7, 144.8, 143.2, 130.1, 124.3, 118.9,

116.7, 114.1, 88.5, 79.7, 72.9, 67.3, 65.1, 55.7, 48.4, 47.2, 45.1, 44.9, 33.5,

29.6, 26.7, 24.3, 23.6, 19.8, 15.2, 13.9, 7.5, 7.4, 7.3, 7.0, 5.7, 5.4; HRMS

(FAB+) calcd for C₄₉H₉₀O₇Si₃N (M + 1) 888.6025, found 888.6052.

To a ﬂask containing crude 50 at 0 °C was added a premixed solution

of HOAc/THF/H₂O (4.0 mL, 8:4:1) dropwise. After 2 h, the solution

was allowed to warm to 10 °C. After 6 h, the reaction was warmed to rt.

After 6 h, the reaction was concentrated in vacuo. Benzene was added

to further dry the product 9 (11.3 mg): ¹H NMR (300 MHz, CDCl₃) δ

7.30 (d, J = 8.8 Hz, 2H), 6.84−6.98 (m, 4H), 6.10 (d, J = 15.9 Hz, 2H),

5.83 (s, 1H), 4.99 (s, 1H), 4.83 (s, 1H), 4.52 (d, J = 10.5 Hz, 1H), 4.12−

4.27 (m, 2H), 3.81 (s, 3H), 3.68−3.80 (m, 3H), 3.16 (m, 1H), 2.59−

2.68 (m, 3H), 2.28−2.38 (m, 1H), 2.21−2.25 (m, 2H), 1.91−2.11 (m,

4H), 1.82 (s, 3H), 1.75 (s, 3H), 1.71−1.82 (m, 4H), 1.64−1.69 (m, 1H),

1.43 (s, 3H), 1.25−1.35 (m, 4H), 1.09 (d, J = 4.0 Hz, 3H), 0.88−1.01

(m, 31H), 0.81 (s, 9H), 0.55−0.68 (m, 18H), 0.09 (s, 3H), 0.01 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ 212.5, 201.2, 168.6, 159.6, 147.0, 145.0,

144.0, 142.1, 132.1, 130.1, 129.9, 128.9, 125.7, 115.5, 113.9, 88.5, 77.3,

72.2, 67.2, 66.1, 55.6, 49.6, 47.0, 46.0, 43.9, 40.3, 39.3, 33.3, 32.3, 31.5,

29.1, 28.6, 26.3, 23.3, 23.5, 23.0, 19.6, 18.3, 14.7, 14.5, 12.5, 7.7, 7.4, 7.3,

7.0, 6.2, 5.6, −3.8, −4.1.

Silyl Ether 49. To a solution of 48 (55 mg, 60 μmol) in CH₂Cl₂

(0.15 mL) at rt was added Et₃N (0.15 mL). The solution was then

cooled to −78 °C. After 5 min, TBSOTf (65.8 mg, 60.4 μL, 0.25 mmol)

was added dropwise. After 5 min, the reaction was warmed to rt. After

20 min, the reaction was quenched with satd aq NH₄Cl (3 mL), and the

mixture was extracted with Et₂O (3 × 10 mL). The dried (MgSO₄)

extract was concentrated in vacuo and puriﬁed by chromatography over

silica gel, eluting with 3% EtOAc/hexanes, to give 49 (53 mg, 53 μmol,

88%) as a colorless oil: [α]²³_D+35.1 (c 0.50, CHCl₃); IR (neat) 2954,

2928, 2876, 1714, 1615, 1515, 1458, 1381, 1250, 1167, 1125, 1065,

1006, 987, 835, 776, 740 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.27 (d,

J = 8.4 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.80 (s, 1H), 5.07 (s, 1H), 4.89

(s, 1H), 4.51 (d, J = 10.5 Hz, 1H), 4.21−4.25 (m, 2H), 3.81 (s, 3H),

3.64−3.81 (m, 3H), 3.17 (dd, J = 9.3, 18.0 Hz, 1H), 2.58 (dd, J = 2.7,

17.7 Hz, 1H), 2.38 (dd, J = 4.5, 16.8 Hz, 1H), 2.19 (dd, J = 6.9, 16.8 Hz,

1H), 2.05−2.10 (m, 2H), 1.86−1.94 (m, 2H), 1.79 (s, 3H), 1.66−1.79

(m, 1H), 1.58−1.62 (m, 1H), 1.40 (s, 3H), 1.28−1.35 (m, 2H), 1.07

(d, J = 6.3 Hz, 3H), 1.05 (d, J = 5.4 Hz, 3H), 0.86−0.97 (m, 30H), 0.78

(s, 9H), 0.50−0.65 (m, 18H), 0.05 (s, 3H), −0.03 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ 212.2, 159.5, 143.6, 143.1, 130.3, 129.9, 124.9,

119.0, 116.6, 113.9, 89.1, 77.3, 72.3, 67.2, 66.1, 55.6, 49.7, 46.4, 45.5,

44.7, 33.7, 29.4, 29.0, 26.3, 24.3, 23.5, 19.7, 18.4, 15.4, 12.9, 7.7, 7.4, 7.3,

5.7, 5.3, −3.7, −4.2; HRMS (FAB+) calcd for C₅₅H₁₀₄O₇Si₄N (M + 1)

1002.6890, found 1002.6923.

Alcohol 52. To a ﬂask containing 13 (120 mg, 0.22 mmol) at 0 °C

was added a premixed solution of HOAc/THF/H₂O (4.0 mL, 8:8:1)

dropwise. After 10 min, the solution was allowed to warm to 5 °C. After

2 h, the reaction was quenched with satd aq NaHCO₃(10 mL)

dropwise. Next, the mixture was extracted with Et₂O (3 × 10 mL), and

the dried (MgSO₄) extract was concentrated in vacuo to give product 52

(90 mg, 0.21 mmol, 95%) as a colorless oil: [α]²³(+) 17.7 (c 0.34,

D

CHCl₃); IR (thin ﬁlm) 3413, 2958, 2910, 2875, 1712, 1613, 1514, 1457,

1

1354, 1302, 1249, 1172, 1076, 1055, 1009, 820, 740 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 7.23 (d, J = 8.4 Hz, 2H) 6.86 (d, J = 8.4 Hz, 2H),

4.43 (d, J = 11.4 Hz, 1H), 4.38 (d, J = 11.4 Hz, 1H), 3.81−3.91 (m, 2H),

3.80 (s, 3H), 3.74 (d, J = 6.3 Hz, 1H), 2.40 (br, 1H), 2.14 (s, 3H), 1.49−

1.65 (m, 2H), 1.32−1.40 (m, 1H), 1.14 (d, J = 6.0 Hz, 3H), 0.85−0.99

(m, 12H), 0.58 (q, J = 7.8 Hz, 6H); ¹³C NMR (400 MHz, CDCl₃) δ

210.8, 159.8, 130.2, 129.7, 114.2, 88.4, 75.3, 72.9, 66.2, 55.7, 43.5, 33.5,

27.5, 24.2, 15.1, 7.4, 5.6; HRMS (FAB+) calcd for C₂₃H₄₁O₅Si (M + 1)

425.2723, found 425.2730.

Ester 53. To a solution of 52 (237 mg, 0.56 mmol), p-NO₂-benzonic

acid (374 mg, 2.24 mmmol), and PPh₃(587 mg, 2.24 mmol) in THF

(3.7 mL) at 0 °C was added DEAD (1.0 mL, 1.04 g, 2.24 mmol, 40%

w/w in PhMe) dropwise. After 10 min, the reaction was warmed to rt.

After 2 h, the reaction was concentrated in vacuo and puriﬁed by

P

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chromatography over silica gel, eluting with 10−15% EtOAc/hexanes,

to give 53 (46 mg, 0.084 mmol, 80%) as a colorless oil: [α]²³_D(+) 38.1

(c 0.48, CHCl₃); IR (thin ﬁlm) 2954, 2875, 1719, 1610, 1528, 1514,

with MeOH (0.2 mL), satd aq tartaric acid (0.2 mL) and H₂O (2.0 mL).

After stirring 12 h at rt, the mixture was extracted with Et₂O (3 ×

10 mL). The dried (MgSO₄) extract was concentrated in vacuo to give

the corresponding crude aldehyde (0.11 mmol).

1

1457, 1349, 1275, 1102, 1036, 1013, 823, 720 cm⁻¹; H NMR (400

MHz, CDCl₃) δ 8.28 (d, J = 8.8 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H), 7.26

(d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.24−5.29 (m, 1H), 4.53

(d, J = 11.2 Hz, 1H), 4.38 (d, J = 11.2 Hz, 1H), 3.80−3.83 (m, 3H), 2.16

(s, 3H), 2.01−2.08 (m, 1H), 1.67−1.69 (m, 1H), 1.55−1.61 (m, 1H),

1.39 (d, J = 6.0 Hz, 3H), 0.93 (t, J = 8.0 Hz, 9H), 0.89 (d, J = 6.8 Hz, 3H),

0.59 (q, J = 8.0 Hz, 6H); ¹³C NMR (400 MHz, CDCl₃) δ 211.3, 164.8,

159.9, 150.8, 136.5, 131.0, 130.3, 129.6, 123.9, 114.2, 87.6, 77.4, 73.1,

71.3, 55.7, 39.9, 33.7, 28.0, 21.4, 14.7, 7.4, 5.5.

To a mixed solution of the above aldehyde (0.11 mmol) in CH₂Cl₂

(0.5 mL) and EtOH (0.5 mL) at 0 °C was added NaBH₄(8.4 mg, 0.22

mmol). After 15 min, the reaction was quenched with a brine solution

(5 mL) and extracted with Et₂O (3 × 10 mL). The dried (MgSO₄)

extract was concentrated in vacuo and puriﬁed by chromatography over

silica gel, eluting with 6% EtOAc/hexanes, to give the corresponding

alcohol intermediate (38 mg, 0.09 mmol, 85%) as a colorless oil.

To a solution of the above alcohol intermediate (29 mg, 0.07 mmol)

in CH₂Cl₂at 0 °C were added sequentially pyridine (21.4 mg, 22.1 μL,

0.27 mmol), DMAP (8.3 mg, 0.07 mmol), and Ac₂O (13.9 mg, 12.8 μL,

0.14 mmol). After 15 min, the reaction was quenched with satd aq

NH₄Cl (5 mL) and extracted with Et₂O (3 × 10 mL). The dried

(MgSO₄) extract was concentrated in vacuo to give product 55 (31 mg,

64 μmol, 94%) as a colorless oil: [α]²³_D(−) 39.3 (c 0.40, CHCl₃); IR

(thin ﬁlm) 3026, 2955, 2913, 2875, 1741, 1496, 1457, 1367, 1236, 1158,

1121, 1053, 1016, 966, 898, 793, 741, 692 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 7.15−7.28 (m, 5H), 6.32 (d, J = 15.9 Hz, 1H), 6.07−6.17 (m,

1H), 5.85 (s, 1H), 4.96 (s, 1H), 4.79 (s, 1H), 3.98−4.07 (m, 2H), 2.41−

2.52 (m, 2H), 2.10 (dd, J = 5.7, 13.5 Hz, 1H), 2.00 (s, 3H), 1.85 (dd, J =

7.8, 13.2 Hz, 1H), 1.79 (s, 3H), 1.58−1.67 (m, 2H), 1.43 (s, 3H), 1.28−

1.36 (m, 1H), 0.97 (t, J = 7.5 Hz, 9H), 0.75(d, J = 6.6 Hz, 3H), 0.61 (q,

J = 7.5 Hz, 6 H); ¹³C NMR (75 MHz, CDCl₃) δ 171.6, 145.3, 143.0,

138.3, 132.0, 128.9, 127.4, 127.3, 126.3, 125.3, 114.9, 78.7, 63.3, 46.4,

46.2, 35.6, 29.0, 27.4, 21.4, 19.6, 15.0, 7.6, 7.2; HRMS (FAB+) calcd for

C₂₉H₄₆O₃SiNa (M + Na) 493.3114, found 493.3130.

Silyl Ether 54. To a solution of 53 (125 mg, 0.23 mmol) in MeOH

(4.7 mL) was added Ba(OH)₂.8H₂O (36.1 mg, 0.12 mmol). After 1 h,

the reaction was quenched with satd aq NH₄Cl (5 mL). The mixture was

extracted with Et₂O (3 × 10 mL). The dried (MgSO₄) extract was

concentrated in vacuo and puriﬁed by chromatography over silica gel,

eluting with 10−15% EtOAc/hexanes, to give an alcohol intermediate

SI-10 (63 mg, 0.15 mmol, 65%) as a colorless oil: [α]²³(+) 38.4

D

(c 1.87, CHCl₃); IR (thin ﬁlm) 3439, 2958, 2933, 2875, 1713, 1613,

1514, 1458, 1376, 1302, 1249, 1079, 1035, 820, 786, 739 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 7.24 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.44

(d, J = 11.4 Hz, 1H), 4.38 (d, J= 11.4 Hz, 1H), 3.75−3.80 (m, 6H), 2.14 (s,

3H), 1.70 (br, 1H), 1.50−1.59 (m, 1H), 1.27−1.35 (m, 2H), 1.16 (d, J = 6.0

Hz, 3H), 0.92 (t, J = 7.8 Hz, 9H), 0.85 (d, J = 6.9 Hz, 3H), 0.58 (q, J = 6.9

Hz, 6H); ¹³C NMR (400 MHz, CDCl₃) δ 211.5, 159.8, 130.2, 129.7, 114.2,

88.3, 73.0, 66.4, 55.7, 43.9, 33.8, 27.7, 24.9, 14.7, 7.4, 5.6; HRMS (FAB+)

calcd for C₂₃H₄₀O₅SiNa (M + Na) 447.2543, found 447.2561.

To a solution of the alcohol intermediate SI-10 (77 mg, 0.18 mmol)

in CH₂Cl₂(0.9 mL) at −78 °C were added 2,6-lutidine (78 mg, 84.8 μL,

0.73 mmol) and TMSOTf (80 mg, 65.2 μL, 0.36 mmol). After 20 min,

the reaction was quenched with satd aq NH₄Cl (5 mL) and extracted

with Et₂O (3 × 10 mL). The dried (MgSO₄) extract was concentrated

in vacuo to give product 54 (80 mg, 0.16 mmol, 90%) as a colorless oil:

Aldehyde 57. To a solution of 55 (31 mg, 66 μmol) in t-BuOH

(0.55 mL) and H₂O (0.55 mL) at rt was added AD mix β*⁵³(92 mg) and

CH₃SO₂NH₂(9.5 mg, 0.10 mmol). After 16 h, the reaction was

quenched with 10% aq Na₂S₂O₃(2 mL). After 30 min, the mixture was

extracted with EtOAc (3 × 10 mL). The dried (MgSO₄) extract was

concentrated in vacuo and puriﬁed by chromatography over silica gel,

eluting with 20% EtOAc/hexanes, to give the corresponding diol

(29 mg, 58 μmol, 88%, 6:1 dr).

[α]²³(+) 31.8 (c 2.80, CHCl₃); IR (thin ﬁlm) 2955, 2911, 2876, 1715,

D

1613, 1514, 1458, 1414, 1372, 1352, 1249, 1124, 1088, 1038, 1006, 820, 787,

741 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.23(d, J = 8.4 Hz, 2H), 6.86 (d, J

= 8.4 Hz, 2H), 4.42 (d, J = 11.4 Hz, 1H), 4.36 (d, J = 11.4 Hz, 1H), 3.74−3.85

(m, 5H), 3.68 (d, J = 6.9 Hz, 1H), 2.09 (s, 3H), 1.55−1.61 (m, 1H), 1.41−

1.50 (m, 1H), 1.25−1.35 (m, 1H), 1.12 (d, J = 6.0 Hz, 3H), 0.92 (t, J = 7.8

Hz, 9H), 0.82 (d, J = 6.6 Hz, 3H), 0.58 (q, J = 7.8 Hz, 6H), 0.07 (s, 9H); ¹³C

NMR (75 MHz, CDCl₃) δ 211.0, 159.7, 130.2, 129.7, 114.1, 89.3, 73.1, 66.2,

55.6, 45.2, 32.4, 26.9, 25.3, 12.9, 7.4, 5.7, 0.7; HRMS (ES+) calcd for

C₂₆H₄₈O₅NaSi₂(M + Na) 519.2938, found 519.2914.

To a solution of the above diol (26 mg, 52 μmol) in THF/Et₂O/H₂O

(1.7 mL, 1:1:1) at rt was added NaIO₄(110 mg, 0.52 mmol). After 2 h,

the reaction was quenched with a brine solution (2 mL) and extracted

with Et₂O (3 × 10 mL). The dried (MgSO₄) extract was concentrated

in vacuo to give the aldehyde 57 (20.4 mg, 52 μmol, 99%) as a colorless

oil. The aldehyde intermediate was applied to the next step without

further puriﬁcation: [α]²³= −11.6 (c 1.83, CHCl₃); IR (neat) 2957,

D

1

2877, 1741, 1724, 1458, 1368, 1239, 1050, 1017, 743 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 9.66 (t, J = 3.0 Hz, 1H), 6.02 (s, 1H), 5.03 (s, 1H),

4.83 (s, 1H), 4.14−4.04 (m, 2H), 2.65 (dd, J = 15.1, 2.9 Hz, 1H), 2.46

(dd, J = 15.1, 3.1 Hz, 1H), 2.14 (dd, J = 13.6, 5.8 Hz, 1H), 2.04 (s, 3H),

1.92 (dd, J = 13.5, 7.8 Hz, 1H), 1.82 (s, 3H), 1.70 −1.60 (m, 2H), 1.48 (s,

3H), 1.45−1.39 (m, 1H), 1.00−0.94 (m, 9H), 0.87 (d, J = 6.5 Hz, 3H),

0.68−0.56 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 203.0, 171.2, 144.3,

141.2, 125.7, 115.1, 62.8, 54.0, 45.8, 35.3, 28.7, 27.9, 20.9, 19.2, 14.7, 7.1,

6.7, 6.6, 5.8; HRMS (EI⁺) calcd for C₂₂H₄₀O₄Si (M⁺) 396.2696, found

396.2678.

Acetate 55. To a solution of 33 (45 mg, 0.11 mmol) in PhMe

(0.53 mL) at −78 °C was added DIBAL-H (0.15 mL, 0.15 mmol, 1.0 M

in PhMe). After 10 min, the reaction was quenched sequentially

Q

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Sultam 60. Following the similar procedure described by Paquette,^38a

Mg (36.0 g, 1.5 mol) was stirred vigorously at rt in a dry ﬂask under Ar. After

120 h, when a black coating formed inside the ﬂask, THF (200 mL) and 1,2-

dibromoethane (2.60 g, 1.2 mL, 13.9 mmol) were added sequentially. After

30 min, a solution of allyl chloride 58 (17.0 g, 75.0 mmol) in THF (80 mL)

was added slowly to the Mg slurry over 5 h. The resulted mixture was stirred

overnight at rt to give 300 mL of Grignard reagent (0.12 M, 47%) as a gray

solution. The concentration of the Grignard reagent was determined by the

titration using menthol in the presence of 1,10-phenanthroline.⁵⁵

(MgSO₄) was concentrated in vacuo to give the alcohol SI-15 (5.6 g,

20.8 mmol, 97%) as a colorless oil: [α]²³= −2.94 (c 0.51, CHCl₃);

D

IR (neat) 3407, 2926, 2868, 1612, 1513, 1461, 1248, 1059, 1036 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 7.29 (d, J = 8.7 Hz, 2H), 6.90

(d, J = 8.7 Hz, 2H), 5.10 (s, 1H), 4.94 (s, 1H), 4.44 (t, J = 12.2 Hz, 2H),

3.91 (t, J = 13.4 Hz, 2H), 3.82 (s, 3H), 3.61−3.78 (m, 2H), 2.15 (dd, J =

13.8, 6.0 Hz, 1H), 1.89−1.96 (m, 1H), 1.89−1.96 (m, 1H), 1.72−1.86

(m, 1H), 1.57−1.69 (m, 1H), 1.23−1.45 (m, 1H), 0.91 (d, J = 6.6 Hz,

3H); ¹³C NMR (75 MHz, CDCl₃) δ 159.2, 144.6, 130.4, 129.3, 113.8,

113.4, 72.6, 71.6, 61.0, 55.3, 41.3, 39.7, 27.5, 19.7, 18.8; HRMS (ES⁺)

calcd for C₁₆H₂₄O₃Na (M + Na) 287.1623, found 287.1649.

Separately, CuBr·SMe₂(7.29 g, 35.5 mmol) and LiCl (1.61 g,

37.9 mmol) were dissolved in THF (80 mL) and added to the solution

of Grinard reagent (263 mL, 31.5 mmol) at −78 °C via syringe. TMSCl

(3.96 g, 4.5 mL, 36.5 mmol) was then added followed by a solution of

known sultam 59⁵⁶(6.9 g, 24.3 mmol) in THF (60 mL). After another

90 min, the reaction was quenched with NH₄Cl−NH₄OH (9:1, pH 9,

60 mL), warmed to rt. The aqueous layer was extracted with EtOAc (3 ×

200 mL). The organic phase was washed with satd aq NaCl (100 mL).

The dried extract (MgSO₄) was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 8−15% EtOAc/hexanes, to

TBS Ether SI-16. To a stirred solution of alcohol SI-15 (5.5 g,

20.8 mmol) in DMF (50 mL) at rt were sequentially added imidazole

(3.4 g, 50.0 mmol) and TBSCl (3.8 g, 25.2 mmol). After 1 h, the reaction

was quenched with satd aq NH₄Cl (50 mL) and extracted with Et₂O

(3 × 150 mL). The dried (MgSO₄) extract was concentrated in vacuo

and puriﬁed by chromatography over silica gel, eluting with 5% EtOAc/

hexanes, to give TBS ether SI-16 (7.7 g, 20.3 mmol, 97%) as a colorless

oil: [α]²³_D= −3.27 (c 1.31, CHCl₃); IR (neat) 2954, 2928, 2856, 1513,

give the product 60 (11.2 g, 34.4 mmol, 97%) as a colorless oil: [α]²³

=

D

−68.0 (c 0.51, CHCl₃); IR (neat) 2959, 2927, 2851, 1693, 1512, 1454,

1328, 1246, 1032 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.28 (d, J = 8.7

Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.12 (s, 1H), 4.96 (s, 1H), 4.44 (t, J =

11.8 Hz, 2H), 3.94 (t, J = 11.8 Hz, 2H), 4.00 (dd, J = 14.0 Hz, 2H), 3.88 (t,

J = 6.2 Hz, 1H), 3.82 (s, 3H), 3.46 (dd, J = 23.0, 13.8 Hz, 2H), 2.78 (dd, J =

16.1, 5.7 Hz, 1H), 2.51 (dd, J = 16.1, 7.6 Hz, 1H), 2.30−2.40 (m, 1H),

2.02−2.15 (m, 4H), 1.82−1.96 (m, 3H), 1.28−1.45 (m, 3H), 1.15 (s, 3H),

0.99 (d, J = 6.4 Hz, 3H), 0.98 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ

171.4, 159.1, 144.1, 130.6, 129.3, 113.7, 113.6, 72.4, 71.7, 65.2, 55.3, 53.0,

48.3, 47.7, 44.7, 42.5, 40.8, 38.6, 32.9, 28.0, 26.5, 20.8, 19.9; HRMS (ES⁺)

calcd for C₂₆H₃₇NO₅SNa (M + Na) 498.2290, found 498.2271.

1

1249, 1094, 835 cm⁻¹; H NMR (300 MHz, CDCl₃) δ 7.29 (d, J =

8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.11 (s, 1H), 4.93 (s, 1H), 4.44 (s,

2H), 3.92 (s, 2H), 3.83 (s, 3H), 3.63−3.70 (m, 2H), 2.13 (dd, J = 13.8, 6.3

Hz, 1H), 1.88−1.96 (m, 1H), 1.76−1.86 (m, 1H), 1.57−1.69 (m, 1H),

1.28−1.35 (m, 1H), 0.91 (s, 9H), 0.89 (d, J = 6.6 Hz, 3H), 0.06 (s, 6H);

¹³C NMR (75 MHz, CDCl₃) δ 159.1, 144.7, 130.6, 129.3, 113.8, 112.8,

72.6, 71.6, 61.3, 55.3, 41.4, 39.8, 27.5, 26.0, 19.6, 18.3, −5.3; HRMS (ES⁺)

calcd for C₂₂H₃₈O₃NaSi (M + Na) 401.2488, found 401.2489.

Aldehyde SI-13. To a stirred solution of sultam 60 (11.0 g,

23.1 mmol) in CH₂Cl₂(115 mL) at −78 °C was added DIBAL-H

(50.8 mL, 50.8 mmol, 1.0 M in CH₂Cl₂). After 2 h, the reaction was

carefully quenched with methanol (2.0 mL) and poured into aq sodium

potassium tartrate (250 mL, 10% aq) at rt. The reaction ﬂask was rinsed

with an additional portion of CH₂Cl₂(150 mL). After 3 h, the aqueous

layer was extracted with CH₂Cl₂(3 × 150 mL). The dried extract

(MgSO₄) was concentrated in vacuo and puriﬁed by chromatography

over silica gel, eluting with 10% EtOAc/hexanes, to give the aldehyde

SI-13 (5.9 g, 22.6 mmol, 98%) as a colorless oil. Further elution with 5%

MeOH/EtOAc gave recovered auxiliary SI-14 (4.9 g, 22.4 mmol, 97%).

Alcohol SI-17. To a stirred solution of TBS ether SI-16 (3.85 g,

10.2 mmol) in CH₂Cl₂/pH 7 buﬀer (10: 1, 110 mL) was added DDQ

(2.77 g, 12.2 mmol) at rt. After 1 h, the reaction was quenched with satd

aq NaHCO₃(50 mL) and extracted with Et₂O (3 × 100 mL). The dried

(MgSO₄) extract was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 8% EtOAc/hexanes, to

give a mixture of product SI-17 and 4-methoxybenzaldehyde (3.90 g,

1:1 mol/mol, 9.9 mmol, 97%) as a colorless oil. An analytically pure

sample was prepared by chromatography over silica gel, eluting with

3−5% EtOAc/hexanes, for characterization, but the product mixture

was used in the subsequent step without complete removal of

SI-13: [α]²³= +5.93 (c 0.91, CHCl₃); IR (neat) 2956, 2929, 2837,

D

1723, 1612, 1513, 1247, 1077, 1034 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ

9.75 (t, J =1.5Hz, 1H), 7.29(d,J =8.7Hz, 2H), 6.90(d, J = 8.7 Hz, 2H), 5.14

(d, J = 1.2 Hz, 1H), 4.95 (s, 1H), 4.44 (s, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.47

(ddd, J = 14.0, 4.0, and 1.3 Hz, 1H), 2.17−2.34 (m, 2H), 2.01−2.11 (m, 2H),

0.98 (d, J = 6.6 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 202.6, 159.2, 143.9,

130.3, 129.3, 114.1, 113.8, 72.4, 71.7, 55.3, 50.6, 41.0, 26.3, 20.1; HRMS (ES⁺)

calcd for C₁₆H₂₂O₃Na (M + Na) 285.1467, found 285.1494.

4-methoxybenzaldehyde. SI-17: [α]²³= −6.09 (c 1.21, CHCl₃); IR

D

(neat) 3338, 2955, 2929, 2858, 1471, 1463, 1255, 1098, 835 cm⁻¹; ¹H

NMR (300 MHz, CDCl₃) δ 5.09 (d, J = 1.5 Hz, 1H), 4.89 (s, 1H), 4.07 (d,

J = 6.3 Hz, 2H), 3.61−3.75 (m, 2H), 2.13 (dd, J = 13.5, 6.0 Hz, 1H), 1.75−

1.95 (m, 2H), 1.55−1.66 (m, 1H), 1.41−1.50 (m, 1H), 1.27−1.38 (m, 1H),

0.91 (s, 9H), 0.89 (d, J = 6.6 Hz, 3H), 0.07 (s, 6H); ¹³C NMR (75 MHz,

CDCl₃) δ 147.6, 110.7, 65.8, 61.2, 41.2, 39.6, 27.6, 26.0, 19.7, 18.3, −5.3;

HRMS (EI⁺) calcd for C₁₄H₃₁O₂Si (M + H) 259.2093, found 259.2091.

Aldohol SI-15. To a stirred solution of aldehyde SI-13 (5.6 g,

21.4 mmol) in CH₂Cl₂(110 mL) at −78 °C was added DIBAL-H

(28.3 mL, 28.3 mmol, 1.0 M in CH₂Cl₂). After 1 h, the reaction was

carefully quenched with methanol (2.0 mL) and poured into aq sodium

potassium tartrate (250 mL, 10% aq) at rt. The reaction ﬂask was rinsed

with an additional portion of CH₂Cl₂(150 mL). After 3 h, the aqueous

layer was extracted with CH₂Cl₂(3 × 150 mL). The dried extract

Aldehyde 61. To a stirred solution of alcohol SI-17 and

4-methoxybenzaldehyde (7.8 g, 1:1 mol/mol, 19.7 mmol) in CH₂Cl₂

(200 mL) were sequentially added NaHCO₃(3.0 g, 35.7 mmol) and

DMP (10.0 g, 23.7 mmol) at rt. After 1 h, the reaction was quenched

with satd aq NaHCO₃(50 mL) and extracted with Et₂O (3 × 150 mL).

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The dried (MgSO₄) extract was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 3% EtOAc/hexanes, to give

aldehyde 61 (4.6 g, 17.7 mmol, 90%) as a colorless oil: [α]²³_D= −8.20 (c

1.21, CHCl₃); IR (neat) 2956, 2929, 2857, 1698, 1255, 1099, 835 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 9.56 (s, 1H), 6.28 (s, 1H), 6.07 (s, 1H),

3.60−3.73 (m, 2H), 2.28 (dd, J = 14.1, 6.9 Hz, 1H), 2.12 (dd, J = 13.8, 8.1

Hz, 1H),1.77−1.86 (m, 1H), 1.53−1.64 (m, 1H), 1.29−1.39 (m, 1H),

0.91 (s, 9H), 0.89 (d, J = 6.6 Hz, 3H), 0.07 (s, 6H); ¹³C NMR (75 MHz,

CDCl₃) δ 194.7, 149.0, 135.2, 61.1, 39.5, 35.2, 28.4, 25.9, 25.5, 19.4, −5.4;

HRMS (EI⁺) calcd for C₁₄H₂₈O₂Si (M) 256.1859, found 256.1861.

portion of Et₂O (50 mL). After 3 h, the aqueous layer was extracted with

Et₂O (3 × 200 mL). The dried extract (MgSO₄) was concentrated in vacuo

and puriﬁed by chromatography over silica gel, eluting with 8% EtOAc/

hexanes, to give allyl alcohol SI-19 (6.20 g, 18.3 mmol, 81%) as a colorless

oil: [α]²³= −36.6 (c 1.66, CHCl₃); IR (neat) 3327, 2954, 2928, 2857,

D

1471, 1462, 1376, 1255, 1098, 1006, 835, 775 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 5.97 (s, 1H), 5.80 (t, J = 6.3 Hz, 1H), 5.08 (s, 1H), 4.87 (s, 1H),

4.34 (d, J = 6.4 Hz, 2H), 3.46−3.72(m, 2H), 2.18(dd, J = 13.6, 6.0 Hz, 1H),

1.99 (d, J = 0.8 Hz, 3H), 1.93 (dd, J = 13.5, 5.2 Hz, 1H), 1.86 (s, 3H), 1.54−

1.73 (m, 2H), 1.28−1.37 (m, 1H), 0.90 (s, 9H), 0.87 (d, J = 6.6 Hz, 3H),

0.05 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 145.2, 139.3, 137.6, 128.1,

125.9, 115.4, 61.3, 60.1, 46.0, 39.7, 28.3, 25.9, 19.5, 18.3, 15.6, 14.2, −5.3;

HRMS (EI⁺) calcd for C₂₀H₃₈O₂Si (M) 338.2641, found 338.2612.

Methyl Ketone SI-18. A solution of aldehyde 61 (4.5 g, 17.5 mmol)

and ylide 62⁵⁷(10.2 g, 30.7 mmol) in toluene (60 mL) was reﬂuxed in

a sealed tube (oil bath 112 °C). After 16 h, the reaction mixture was

concentrated in vacuo and puriﬁed by chromatography over silica gel,

eluting with 5% EtOAc/hexanes (1% Et₃N added), to give diene SI-18

(5.0 g, 16.1 mmol, 92%) as a slightly yellow oil: [α]²³_D= −41.1 (c 0.53,

CHCl₃); IR (neat) 2955, 2928, 2857, 1671, 1255, 1100, 836, 775 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 6.90 (s, 1H), 5.29 (s, 1H), 5.14 (s, 1H),

3.62−3.73 (m, 2H), 2.37 (s, 3H), 2.30 (dd, J = 10.2, 4.8 Hz, 1H), 2.05 (dd,

J = 10.5, 6.3 Hz, 1H), 1.97 (d, J = 10.2 Hz, 3H), 1.71−1.78 (m, 1H), 1.59−

1.64 (m, 1H), 1.34−1.38 (m, 1H), 0.91 (s, 9H), 0.89 (d, J = 6.6 Hz, 3H),

0.07 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 200.3, 143.7, 140.9, 137.8,

118.9, 61.0, 45.1, 39.6, 28.4, 25.9, 25.7, 19.3, 18.3, 13.1, −5.3; HRMS

(FAB⁺) calcd for C₁₈H₃₅O₂Si (M + H) 311.2406, found 311.2400.

Epoxide 64. To a stirred solution of (+)-DIPT (41.5 mg, 0.18

mmol) and 4 Å molecular sieves (about 200 mg) in CH₂Cl₂(4.0 mL)

were sequentially added Ti(O-i-Pr)₄(34 mg, 34.6 μL, 0.12 mmol) and

TBHP (236 μL, 1.30 mmol, 5.0−6.0 M in decane) at −20 °C. After 20 min,

the reaction mixture was cooled to −78 °C, and a precooled solution (−78

°C) of allyl alcohol SI-19 (200 mg, 0.59 mmol) in CH₂Cl₂(4.0 mL) was

added via cannula. The resulted solution was warmed to −50 °C. After

another 60 min, the reaction was quenched with pH 7 phosphate buﬀer (0.5

mL), ﬁltered over Celite, and extracted with Et₂O (3 × 20 mL). The dried

organic layers (MgSO₄) were concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 10% EtOAc/hexanes, to give

epoxide 64 (167 mg, 0.47 mmol, 80%) as a colorless oil: [α]²³_D= −17.3 (c

1.66, CHCl₃); IR (neat) 3430, 2954, 2927, 2856, 1471, 1463, 1378, 1255,

1097, 836, 775 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 5.89 (s, 1H), 5.03 (s,

1H), 4.86 (s, 1H), 3.86−3.92 (m, 1H), 3.73−3.81 (m, 1H), 3.62−3.71 (m,

2H), 3.02 (dd, J = 10.5, 6.3 Hz, 1H), 2.14 (dd, J = 13.5, 5.6 Hz, 1H), 1.91

(dd, J = 13.5, 8.4 Hz, 1H), 1.84 (d, J = 1.1 Hz, 3H), 1.54−1.66 (m, 2H), 1.45

(s, 3H), 1.27−1.34 (m, 1H), 0.91 (s, 9H), 0.83 (d, J = 6.4 Hz, 3H), 0.06 (s,

6H); ¹³C NMR (75 MHz, CDCl₃) δ 144.0, 137.5, 126.2, 115.2, 63.7, 61.3,

45.6, 39.8, 28.2, 26.0, 19.3, 18.3, 16.7, 14.8, −5.3; HRMS (CI⁺) calcd for

C₂₀H₃₉O₃Si (M + H) 355.2669, found 355.2666.

Triene Ester 63. To a stirred slurry of NaH (1.29 g, 32.2 mmol) in

DME (50 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (6.48 g,

5.74 mL, 28.9 mmol) at rt. After 1 h, a solution of methyl ketone SI-18

(5.00 g, 16.1 mmol) in DME (25 mL) was added. The resulted solution

was reﬂuxed for 3 h and then quenched with H₂O (15 mL) and extracted

with Et₂O (3 × 150 mL). The dried extract (MgSO₄) was concentrated

in vacuo and puriﬁed by chromatography over silica gel, eluting with 2%

EtOAc/hexanes (1% Et₃N added), to give triene ester 63 (4.42 g, 11.6

mmol, 70%) as a colorless oil: [α]²³_D= −34.7 (c 1.66, CHCl₃); IR (neat)

1

2955, 2928, 2857, 1716, 1610, 1255, 1163, 1098, 836, 775 cm⁻¹; H

NMR (300 MHz, CDCl₃) δ 6.24 (s, 1H), 5.92 (s, 1H), 5.13 (s, 1H), 4.93

(s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.61−3.68 (m, 2H), 2.36 (s, 3H), 2.20

(dd, J = 13.3, 5.9 Hz, 1H), 1.93−2.00 (m, 4H), 1.53−1.71 (m, 2H), 1.31

(t, J = 7.2 Hz, 3H), 0.89 (s, 9H), 0.87 (d, J = 6.9 Hz, 3H), 0.05 (s, 6H);

¹³C NMR (100 MHz, CDCl₃) δ 167.4, 156.4, 144.7, 137.8, 132.4, 116.4,

115.9, 61.2, 59.7, 45.7, 39.7, 28.3, 25.9, 19.5, 18.3, 15.8, 15.5, 14.4, −5.3;

HRMS (EI⁺) calcd for C₂₂H₄₀O₃Si (M + H) 380.2747, found 380.2732.

Diol 65. To a stirred solution of epoxide 64 (1.5 g, 4.23 mmol) in

THF (30 mL) was added Red-Al (1.5 mL, 9.91 mmol, 65% w/v in

toluene) at 0 °C. After 1 h, another portion of Red-Al (1.5 mL,

9.91 mmol, 65% w/v in toluene) was added. After another 1.5 h, the reaction

was quenched with H₂O (0.10 mL), and extracted with CH₂Cl₂(3 ×

150 mL). The dried organic layers (MgSO₄) was concentrated in vacuo

and puriﬁed by chromatography over silica gel, eluting with

6−12% EtOAc/hexanes (1% Et₃N added), to give diol 65 (1.05 g, 2.96

mmol, 70%) as a colorless oil: [α]²³_D= −29.4 (c 0.81, CHCl₃); IR (neat)

3389, 2955, 2928, 2858, 1471, 1462, 1382, 1255, 1097, 836, 775 cm⁻¹; ¹H

NMR (300 MHz, CDCl₃) δ 6.10 (s, 1H), 5.04 (d, J = 0.9 Hz, 1H), 4.84 (s,

1H), 3.62−3.77(m, 4H), 3.04(s, br, 1H), 2.60(s, br, 1H), 2.16(dd,J =13.2,

5.1 Hz, 1H), 1.88−1.96 (m, 3H), 1.79 (d, J = 0.9 Hz, 3H), 1.55−1.70 (m,

2H), 1.37 (s, 1H), 1.27−1.34 (m, 1H), 0.91 (s, 9H), 0.86 (d, J = 6.5 Hz, 3H),

0.07 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 145.1, 141.7, 125.1, 114.4, 77.1,

61.6, 60.4, 46.1, 40.1, 39.7, 28.6, 28.2, 26.0, 19.6, 18.4, 15.1, −5.2; HRMS

(ES⁺) calcd for C₂₀H₄₀O₃SiNa (M + Na) 379.2644, found 379.2643.

Allyl Alcohol SI-19. To a stirred solution of triene ester 63 (8.61 g,

22.6 mmol) in THF (200 mL) was added DIBAL-H (46 mL, 46.0 mmol,

1 M in toluene) at −78 °C. After 1.5 h, the reaction was quenched

with MeOH (1.0 mL) and poured into aq sodium potassium tartrate

(350 mL, 10% aq) at rt. The reaction ﬂask was rinsed with an additional

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Aldehyde 57. TES ether 67 (2.1 mg, 4.09 mmol) was dissolved in a

stirred solution of HOAc/THF/H₂O (34 mL, 8:8:1) at 0 °C. After 1.5 h,

the reaction was then quenched with solid NaHCO₃and extracted with

ether (4 × 50 mL). The dried extract (MgSO₄) was concentrated in

vacuo to aﬀord crude alcohol (2.0 g), which was used in the next step

without further puriﬁcation.

To a stirred solution of crude alcohol (2.0 g) in CH₂Cl₂(20 mL) were

added sequentially solid NaHCO₃(1.0 g, 11.9 mmol) and DMP (2.16 g,

5.09 mmol) at rt. After 1 h, the reaction was quenched with satd aq

NaHCO₃(15 mL) and extracted with ether (3 × 40 mL). The dried

extract (MgSO₄) was concentrated in vacuo andpuriﬁed by chromatog-

raphy over silica gel, eluting with 5% EtOAc/hexanes, to give aldehyde

57 (1.36 g, 3.43 mmol, 74% over two steps) as a colorless oil.

Ester 66. To a stirred solution of diol 65 (2.10 g, 5.89 mmol) in

CH₂Cl₂(50 mL) were sequentially added pyridine (1.37 g, 1.40 mL,

17.7 mmol) and trichloroacetyl chloride (1.29 g, 0.79 mL, 7.09 mmol).

After 3 h, the reaction was quenched with satd aq NH₄Cl (10 mL) and

extracted with ether (3 × 30 mL). The dried extract (MgSO₄) was

concentrated in vacuo to give crude ester (3.30 g) as a colorless oil,

which was used in the next step without further puriﬁcation.

To a stirred solution of crude ester (3.30 g) in CH₂Cl₂/EtOH (1:1,

50 mL) was added CSA (2.31 g, 9.88 mmol) at 0 °C. After 1.5 h, the

reaction was quenched with satd aq NaHCO₃(10 mL) and extracted

with ether (3 × 40 mL). The dried extract (MgSO₄) was concentrated in

vacuo to give crude diol (2.02 g), which was used in the next step

without further puriﬁcation.

To a stirred solution of crude diol (2.02 g) in CH₂Cl₂(50 mL) were

added sequentially pyridine (1.53 g, 1.57 mL, 19.5 mmol) and Ac₂O

(0.99 g, 0.92 mL, 9.73 mmol). After 1.5 h, the reaction was quenched

with satd aq NH₄Cl (10 mL) and extracted with ether (3 × 40 mL).

The dried extract (MgSO₄) was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 10% EtOAc/hexanes, to

Aldol Product SI-20. To a solution of methyl ketone 54 (38 mg,

76 μmol) in Et₂O (0.4 mL) at −78 °C was added LDA⁵⁴(85.0 μL, 1.0 M in

THF). After 20 min, a precooled (−78 °C) solution of aldehyde intermediate

(20 mg, 50 μmol) in Et₂O (0.25 mL) was transferred in one portion via

cannula at −78 °C. After 20 min, the reaction was quenched with satd aq

NH₄Cl (3 mL) and extracted with Et₂O (3 × 10 mL). The dried (MgSO₄)

extract was concentrated in vacuo and puriﬁed by chromatography over silica

gel, eluting with 5% EtOAc/hexanes, to give the alcohol intermediate SI-20

(28 mg, 31 μmol, 62%) as a colorless oil: [α]²³_D(+) 15.7 (c 1.55, CHCl₃); IR

(neat) 3515, 2955, 2912, 2876, 1741, 1717, 1615, 1515, 1417, 1368, 1247,

1117, 1037, 1008, 899, 806, 741 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.28

(d, J = 9.0 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.87 (s, 1H), 5.01 (s, 1H), 4.83

(s, 1H), 4.50 (d, J = 11.1 Hz, 1H), 4.34−4.51 (m, 1H), 4.33 (d, J = 11.1 Hz,

1H), 4.04−4.14 (m, 2H), 3.80 (s, 3H), 3.71−3.78 (m, 3H), 3.03 (dd, J = 7.5,

17.4 Hz, 1H), 2.29 (dd, J = 4.5, 17.4 Hz, 1H), 2.12 (dd, J = 5.7, 8.7 Hz, 1H),

2.03 (s, 3H), 1.83−1.96 (m, 2H), 1.82 (s, 3H), 1.59−1.73 (m, 3H), 1.52 (s,

3H), 1.42−1.49 (m, 4H), 1.11 (d, J = 6.0 Hz, 3H), 0.86−0.98 (m, 21H), 0.82

(d, J = 6.6 Hz, 3H), 0.51−0.67 (m, 12H), 0.06 (s, 9H); ¹³C NMR (75 MHz,

CDCl₃) δ 211.7, 171.6, 159.6, 144.6, 143.8, 130.3, 130.1, 125.2, 115.6, 114.0,

88.4, 79.8, 77.6, 72.8, 66.2, 65.1, 63.3, 55.6, 48.5, 46.7, 46.2, 44.8, 35.7, 32.5,

29.1, 26.5, 25.2, 21.4, 19.7, 15.1, 13.3, 7.5, 7.4, 7.0, 5.7, 0.7; HRMS (ES+)

calcd for C₄₈H₈₈O₉Si₃Na (M + Na) 915.5634, found 915.5564.

give 66 (1.90 g, 4.42 mmol, 75% over 3 steps) as a colorless oil: [α]²³

=

D

−14.1 (c 1.16, CHCl₃); IR (neat) 3481, 2962, 2928, 1766, 1739, 1720,

1458, 1368, 1247, 828, 682 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 6.01

(s, 1H), 5.04 (s, 1H), 4.85 (s, 1H), 4.47−4.36 (m, 2H), 4.15−4.06 (m,

2H), 2.12−2.02 (m, 3H), 2.03 (s, 3H), 1.97−1.89 (m, 3H), 1.83 (s, 3H),

1.70−1.60 (m, 2H), 1.50−1.38 (m, 1H), 1.41 (s, 3H), 0.89 (d, J = 6.3

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.2, 161.9, 144.1, 141.4,

124.9, 115.3, 74.6, 66.5, 62.3, 45.6, 37.8, 35.2, 28.7, 28.3, 21.0, 19.4, 14.9;

HRMS (EI⁺) calcd for C₁₈H₂₇O₅Cl₃(M⁺) 428.0924, found 428.0932.

TES Ether 67. To a stirred solution of alcohol 66 (1.90 g, 4.4 mmol)

in CH₂Cl₂/EtOH (1:1, 50 mL) was added NH₃·H₂O (15 mL) at rt.

After 1 h, the reaction was quenched with satd aq NH₄Cl (15 mL) and

extracted with ether (3 × 40 mL). The dried extract (MgSO₄) was

concentrated in vacuo to aﬀord crude diol (1.55 g), which which was

used in the next step without further puriﬁcation.

To a stirred solution of crude diol (1.55 g) in CH₂Cl₂/Et₃N (1:1, 30 mL)

was added freshly distilled TESOTf (3.52 g, 3.01 mL, 13.1 mmol) at −78 °C.

After 20 min, the reaction was quenched with satd aq NaHCO₃(10 mL) and

extracted with ether (3 × 40 mL). The dried extract (MgSO₄) was

concentrated in vacuo andpuriﬁed by chromatography over silica gel, eluting

with 2% EtOAc/hexanes, to give TES ether 67 (2.12 g, 4.09 mmol, 93% over

two steps) as a colorless oil: [α]²³= −18.4 (c 1.11, CHCl₃); IR (neat)

D

1

29554, 2912, 2876, 1748, 1458, 1238, 1086, 1016, 741 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 5.89 (s, 1H), 5.00 (d, J = 1.2 Hz, 1H), 4.81 (d, J = 1.2

Hz, 1H), 4.18−4.05 (m, 2H), 3.72−3.63 (m, 1H), 3.54−3.41 (m, 1H),

2.15 (dd, J = 13.5, 5.4 Hz, 1H), 2.05 (s, 3H), 1.95−1.89 (m, 2H), 1.87−

1.78 (m, 1H), 1.77 (d, J = 1.2 Hz, 3H), 1.71−1.58 (m, 2H), 1.49−1.39 (m,

1H), 1.42 (s, 3H), 1.12−0.91 (m, 18H), 0.87 (d, J = 6.6 Hz, 3H), 0.74−

0.50 (m, 12H); ¹³C NMR (100 MHz, CDCl₃) δ 171.1, 144.8, 142.3, 124.3,

114.4, 77.2, 62.3, 59.5, 46.0, 44.4, 35.3, 28.8, 27.8, 21.0, 19.3, 14.6, 7.2, 6.9,

6.8, 6.4, 5.8, 4.4; HRMS (EI⁺) calcd for C₂₈H₅₆O₄Si₂Na (M + Na)

535.3615, found 535.3637.

TES Ethers 68 and 69. To a solution of the above alcohol

intermediate (40 mg, 45 μmol) in CH₂Cl₂(0.15 mL) and Et₃N (0.15 mL)

at −78 °C was added TESOTf (32.0 mg, 28.3 μL, 0.12 mmol). After

T

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20 min, the reaction was quenched with satd aq NH₄Cl (3 mL). The

mixture was extracted with Et₂O (3 × 10 mL), and the dried (MgSO₄)

extract was concentrated in vacuo to give 69 (36 mg, 36 μmol, 82%) as a

colorless oil: [α]²³_D(+) 18.6 (c 1.58, CHCl₃); IR (neat) 2955, 2926, 2876,

2855, 1742, 1716, 1615, 1515, 1458, 1366, 1249, 1127, 1084, 1006, 899,

835, 776, 741 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.4 Hz,

2H), 6.88 (d, J = 8.4 Hz, 2H), 5.84 (s, 1H), 5.04 (s, 1H), 4.89 (s, 1H), 4.59

(d, J = 10.8 Hz, 1H), 4.29−4.35 (m, 1H), 4.27 (d, J = 10.8 Hz, 1H), 4.10−

4.17 (m, 2H), 3.84 (s, 4H), 3.76−3.78 (m, 1H), 3.71 (d, J = 7.2 Hz, 1H),

3.19 (dd, J = 8.4, 17.6 Hz, 1H), 2.54 (dd, J = 3.3, 17.6 Hz, 1H), 2.11−2.15

(m, 1H), 2.06 (s, 3H), 1.86−1.98 (m, 2H), 1.85 (s, 3H), 1.63−1.77 (m,

4H), 1.52−1.56 (m, 1H), 1.45 (s, 3H), 1.30−1.38 (m, 2H), 1.13 (d, J = 6.4

Hz, 3H), 0.83−0.98 (m, 30H), 0.86 (d, J = 6.4 Hz, 3H), 0.52−0.64 (m,

18H), 0.15 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 211.3, 171.2, 159.1,

144.4, 142.6, 130.1, 129.7, 125.1, 115.0, 113.5, 88.2, 77.4, 76.4, 72.0, 65.9,

63.0, 55.3, 50.0, 46.5, 46.0, 44.0, 35.3, 32.3, 29.7, 28.7, 28.0, 24.7, 21.0, 19.3,

14.9, 13.3, 7.3, 7.1, 7.0, 6.8, 6.6, 6.4, 5.3, 5.1, 0.4; HRMS (ES+) calcd for

C₅₄H₁₀₂O₉Si₄Na (M + Na) 1029.6499, found 1029.6470.

3.72 (d, J = 6.0 Hz, 1H), 3.16 (dd, J = 8.8, 17.6 Hz, 1H), 3.12 (s, 1H),

3.07 (s, 1H), 2.67 (t, J = 7.2 Hz, 2H), 2.60 (dd, J = 2.8, 17.6 Hz, 1H), 2.16

(dd, J = 7.6, 14.8 Hz, 2H), 2.08−2.12 (m, 1H), 2.06 (s, 3H), 1.83−1.94

(m, 4H), 1.83 (s, 3H), 1.81 (s, 3H), 1.61−1.77 (m, 5H), 1.52−1.55 (m,

1H), 1.43 (s, 3H), 1.40−1.43 (m, 1H), 1.36 (t, J = 6.8 Hz, 6H), 1.22 (d,

J = 6.0 Hz, 3H), 0.90−1.00 (m, 30H), 0.86 (d, J = 6.4 Hz, 3H), 0.54−

0.66 (m, 18H); ¹³C NMR (100 MHz, CDCl₃) δ 211.7, 201.5, 201.4,

171.2, 167.7, 159.2, 144.5, 142.3, 140.6, 129.9, 129.7, 129.0, 125.2, 115.0,

113.6, 87.4, 76.0, 72.0, 68.9, 66.0, 63.1, 62.6, 62.5, 55.3, 49.9, 46.8, 45.9,

43.4, 43.1, 41.8, 39.3, 35.3, 33.0, 28.7, 28.2, 27.7, 22.3, 21.0, 20.8, 19.3,

16.4, 16.3, 14.9, 14.1, 12.5, 7.3, 7.0, 6.9, 6.8, 5.2, 5.1; HRMS (ES+) calcd

for C₆₄H₁₁₅O₁₄PSi₃Na (M + Na) 1245.7230, found 1245.7181.

Alcohol 72. To a ﬂask containing 71 (50.0 mg, 41 μmol) at rt was

added a premixed solution of Ba(OH)₂·8H₂O (1.5 mL, 0.1 M in

MeOH). After 10 min, the mixture was puriﬁed by chromatography over

silica gel, eluting with 50% EtOAc/hexanes, to give 72 (42 mg, 36 μmol,

88%) as a colorless oil: [α]²³_D(+) 19.8 (c 0.78, CHCl₃); IR (neat) 3444,

2954, 2929, 2876, 1713, 1614, 1515, 1458, 1379, 1251, 1165, 1125,

1059, 1024, 970, 900, 835, 809, 741 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)

δ 7.33 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.69 (t, J = 7.6 Hz,

1H), 5.85 (s, 1H), 5.03−5.06 (m, 2H), 4.85 (s, 1H), 4.62 (d, J = 10.4 Hz,

1H), 4.12−4.27 (m, 7H), 3.84 (s, 3H), 3.81 (dd, J = 3.2, 6.8 Hz, 1H)

3.70−3.76 (m, 3H), 3.19 (dd, J = 9.2, 17.2 Hz, 1H), 3.13 (s, 1H), 3.07 (s,

1H), 2.68 (t, J = 7.2 Hz, 2H), 2.60 (dd, J = 2.8, 17.6 Hz, 1H), 2.18 (q, J =

7.6 Hz, 2H), 2.10 (dd, J = 5.2, 18.4 Hz, 1H), 1.83−1.91 (m, 3H), 1.83 (s,

3H), 1.81 (s, 3H), 1.51−1.81 (m, 7H), 1.43 (s, 3H), 1.38−1.43 (m, 1H),

1.36 (t, J = 7.2 Hz, 6H), 1.23 (d, J = 6.0 Hz, 3H), 0.87−1.00 (m, 33H),

0.54−0.66 (m, 18H); ¹³C NMR (100 MHz, CDCl₃) δ 212.3, 201.5,

201.4, 167.7, 159.2, 144.9, 141.7, 140.7, 130.0, 129.7, 129.0, 125.6, 114.9,

113.5, 87.6, 77.5, 75.9, 72.0, 68.9, 66.2, 62.6, 62.5, 61.0, 55.3, 49.5, 46.6,

46.2, 43.4, 43.1, 41.8, 40.1, 39.5, 32.9, 29.7, 28.4, 28.3, 27.7, 22.3, 20.8,

19.2, 16.4, 16.3, 15.1, 14.1, 13.9, 12.5, 7.3, 7.0, 6.9, 6.8, 5.2, 5.1; HRMS

(ES+) calcd for C₆₂H₁₁₃O₁₃PSi₃Na (M + Na) 1203.7124, found

1203.7054.

Alcohol 70. To a ﬂask with 69 (180 mg, 0.18 mmol) at 0 °C was

added a freshly prepared stock solution of HOAc/THF/H₂O (3.0 mL,

8:8:1) dropwise. After 40 min, the reaction was quenched with satd

aq NaHCO₃(20 mL) carefully and extracted with Et₂O (3 × 10 mL).

The dried (MgSO₄) extract was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 5% EtOAc/hexanes, to give

70 (102 mg, 0.11 mmol, 61%) as a colorless oil: [α]²³_D(+) 23.7 (c 0.60,

CHCl₃); IR (neat) 3546, 2955, 2926, 2876, 2855, 1742, 1716, 1615,

1515, 1458, 1366, 1249, 1127, 1084, 1006, 899, 835, 776, 741 cm⁻¹; ¹H

NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz,

2H), 5.87 (s, 1H), 5.02 (s, 1H), 4.86 (s, 1H), 4.55 (d, J = 10.8 Hz, 1H),

4.23−4.29 (m, 1H), 4.23 (d, J = 10.8 Hz, 1H), 4.12−4.17 (m, 2H), 3.85

(s, 4H), 3.75−3.85 (m, 3H), 3.18 (dd, J = 9.2, 17.6 Hz, 1H), 2.54 (dd, J =

2.8, 17.6 Hz, 1H), 2.13 (dd, J = 5.6, 13.6 Hz, 1H), 2.06 (s, 3H), 1.86−

1.94 (m, 2H), 1.83 (s, 3H), 1.63−1.80 (m, 4H), 1.52−1.56 (m, 1H),

1.45 (s, 3H), 1.38−1.45 (m, 2H), 1.19 (d, J = 6.0 Hz, 3H), 0.88−1.01

(m, 33H), 0.55−0.68 (m, 18H); ¹³C NMR (100 MHz, CDCl₃) δ 211.3,

171.2, 159.1, 144.9, 141.7, 130.0, 129.8, 125.5, 114.9, 113.5, 88.5, 77.4,

77.2, 76.4, 71.8, 65.8, 63.2, 55.3, 49.5, 46.2, 45.8, 44.1, 35.4, 33.2, 29.7,

28.7, 28.5, 24.5, 21.0, 19.3, 14.9, 13.6, 7.3, 7.0, 6.95, 6.87, 5.2, 5.1; HRMS

(ES+) calcd for C₅₁H₉₄O₉Si₃Na (M + Na) 957.6103, found 957.6157.

Macrolactone 51. To a solution of 72 (42 mg, 36 μmol) in CH₂Cl₂

(1.2 mL) at rt. was added TPAP (15 mg, 43 μmol). After 1 h, THF

(3.3 mL), H₂O (82.8 μL) and Ba(OH)₂·8H₂O (43 mg, 0.13 mmol)

were sequentially added to the reaction. After 3 h, the reaction was

directly puriﬁed by chromatography over silica gel, eluting with 5%

EtOAc/hexanes, to give 51 (30.6 mg, 30 μmol, 85%) as a colorless oil:

[α]²³_D(+) 1.6 (c 0.45, CHCl₃); IR (neat) 2954, 2925, 2875, 2854, 1710,

1673, 1614, 1515, 1461, 1377, 1251, 1171, 1120, 1068, 1018, 985, 835,

808, 742 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.6 Hz, 2H),

6.94−7.01 (m, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.71 (t, J = 7.6 Hz, 1H),

6.09 (d, J = 16.0 Hz, 1H), 5.77 (s, 1H), 5.05 (s, 1H), 4.96−5.04 (m, 1H),

4.87 (s, 1H), 4.53 (d, J = 10.8 Hz, 1H), 4.21−4.27 (m, 1H), 4.21 (d, J =

10.8 Hz, 1H), 3.84 (s, 3H), 3.67−3.74 (m, 2H), 3.15 (dd, J = 9.2, 17.6

Hz, 1H), 2.56−2.67 (m, 3H), 2.08−2.27 (m, 3H), 1.90 (s, 3H), 1.78 (s,

3H), 1.47−1.78 (m, 9H), 1.43 (s, 3H), 1.26−1.42 (m, 2H), 1.25 (d, J =

6.0 Hz, 3H), 0.90−1.00 (m, 30H), 0.83 (d, J = 6.4 Hz, 3H), 0.54−0.66

(m, 18H); ¹³C NMR (100 MHz, CDCl₃) δ 209.8, 200.8, 167.6, 159.2,

147.0, 144.5, 142.7, 140.8, 132.3, 130.0, 129.5, 129.2, 125.3, 115.5, 113.6,

Ketophosphonate 71. To a solution of phosphonate acid 11

(74 mg, 0.24 mmol) in PhMe (0.5 mL) at rt was added triethylamine

(26.2 mg, 36.0 μL, 0.24 mmol) and 2,4,6-trichlorobenzoyl chloride

(56 mg, 36.0 μL, 0,24 mmol). After 6 h, solvent of the reaction was

removed in vacuo. A solution of the alcohol 70 (60 mg, 64 μmol) in

PhMe (0.5 mL) was transferred into the above ﬂask via cannula and

DMAP (29.6 mg, 0.24 mmol) were added sequentially. After 16 h, the

reaction was puriﬁed by chromatography over silica gel, eluting with

70% EtOAc/hexanes, to give 71 (50 mg, 41 μmol, 64%) as a colorless

oil: [α]²³_D(+) 25.3 (c 1.50, CHCl₃); IR (neat) 2954, 2933, 2876, 1739,

1712, 1613, 1515, 1461, 1366, 1251, 1165, 1124, 1026, 968, 901, 835,

770, 741 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, J = 8.8 Hz, 2H),

6.88 (d, J = 8.8 Hz, 2H), 6.69 (t, J = 7.2 Hz, 1H), 5.85 (s, 1H), 5.03 (br,

2H), 4.88 (s, 1H), 4.62 (d, J = 10.8 Hz, 1H), 4.25−4.31 (m, 1H), 4.25 (d,

J = 10.8 Hz, 1H), 4.05−4.21 (m, 6H), 3.84 (s, 3H), 3.81−3.83 (m, 1H),

U

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87.9, 71.7, 68.9, 65.4, 55.3, 49.2, 47.1, 45.8, 41.8, 40.6, 37.4, 32.0, 31.5,

31.4, 27.4, 22.9, 21.0, 19.5, 15.2, 14.2, 12.5, 7.3, 7.0, 6.9, 6.8, 5.2, 5.1;

HRMS (ES+) calcd for C₅₈H₁₀₀O₉Si₃Na (M + Na) 1047.6573, found

1047.6494.

(m, 4H), 1.89−1.92 (m, 1H), 1.89 (s, 3H), 1.84 (s, 3H), 1.75−1.86 (m,

3H), 1.53−1.70 (m, 7H), 1.45 (s, 3H), 1.30−1.36 (m, 1H), 1.26 (d, J =

5.6 Hz, 3H), 0.91−1.01 (m, 30H), 0.56−0.67 (m, 18H); ¹³C NMR (100

MHz, CDCl₃) δ 210.8, 167.8, 159.2, 144.7, 142.4, 141.2, 129.9, 129.8,

128.9, 125.6, 115.4, 113.6, 88.1, 77.1, 71.8, 68.7, 68.2, 65.4, 61.3, 55.3,

54.2, 49.8, 46.5, 45.4, 41.8, 39.5, 33.3, 31.1, 30.8, 28.5, 27.7, 24.1, 21.1,

20.1, 15.1, 12.5, 11.8, 7.3, 7.0, 6.9, 5.3, 5.1; HRMS (ES+) calcd for

C₅₈H₁₀₂O₁₀Si₃Na (M + Na) 1065.6679, found 1065.6774.

Allylic Alcohol 75. To a solution of (S)-2-methyl-CBS-oxazabor-

olidine (10.1 μL, 10 μmol, 1.0 M in PhMe) in CH₂Cl₂(0.3 mL) at rt

was added catechol borane (0.20 mL, 0.20 mmol, 1.0 M CH₂Cl₂). After

10 min, the resulted solution was cooled to −20 °C. A solution

of macrolactone 51 (26 mg, 25 μmol) in CH₂Cl₂(0.65 mL) was added

into the above solution dropwise via cannula. After 2 h, the reaction

was quenched with MeOH (2.0 mL) and concentrated in vacuo. The

resultant mixture was puriﬁed by preparative TLC, eluting with 25%

EtOAc/hexane, to give 75 (14 mg, 14 μmol, 56%) as a colorless oil:

[α]²³_D(+) 7.6 (c 0.88, CHCl₃); IR (neat) 3459, 2954, 2917, 2875, 2849,

1709, 1614, 1515, 1461, 1377, 1251, 1173, 1125, 1070, 1018, 835, 776,

743 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.6 Hz, 2H), 6.89

(d, J = 8.6 Hz, 2H), 6.72 (t, J = 7.6 Hz, 1H), 5.79 (s, 1H), 5.68−5.72 (m,

1H), 5.49 (dd, J = 6.8, 15.2 Hz, 1H), 5.05 (s, 1H), 4.97−5.04 (m, 1H),

4.87 (s, 1H), 4.57 (d, J = 10.8 Hz, 1H), 4.28−4.32 (m, 1H), 4.22 (d, J =

10.8 Hz, 1H), 4.13−4.17 (m, 1H), 3.85 (s, 3H), 3.65−3.73 (m, 2H),

3.16 (dd, J = 9.2, 18.0 Hz, 1H), 2.53 (dd, J = 3.2, 18.0 Hz, 1H), 2.21−

2.24 (m, 4H), 1.98−2.04 (m, 4H), 1.88 (s, 3H), 1.82 (s, 3H), 1.75−1.84

(m, 2H), 1.53−1.70 (m, 7H), 1.44 (s, 3H), 1.30−1.36 (m, 1H), 1.24 (d,

J = 5.6 Hz, 3H), 0.89−1.00 (m, 30H), 0.82 (d, J = 6.0 Hz, 3H), 0.54−

0.66 (m, 18H); ¹³C NMR (100 MHz, CDCl₃) δ 210.6, 167.8, 159.2,

145.1, 142.6, 141.7, 134.5, 130.4, 129.9, 129.8, 128.5, 125.6, 115.1, 113.5,

88.1, 77.2, 76.6, 72.4, 71.7, 68.6, 65.5, 55.3, 53.5, 49.5, 46.4, 44.9, 41.1,

39.4, 36.6, 32.2, 31.4, 28.6, 27.5, 23.7, 21.1, 19.8, 15.0, 12.6, 11.9, 7.3, 7.0,

6.9, 6.8, 5.2, 5.1; HRMS (ES+) calcd for C₅₈H₁₀₂O₉Si₃Na (M + Na)

1049.6729, found 1049.6678.

Selenide 78. To a solution of vinyl epoxide 76 (5.0 mg, 5 μmol)

in THF (0.15 mL) at rt were added 77 (33 mg, 0.15 mmol) and PBu₃

(29 mg, 36.2 μL, 0.15 mmol). After 1 h, the reaction mixture was directly

puriﬁed by preparative TLC, eluting with 25% EtOAc/hexane, to give

selenide 78 (3.0 mg, 2.5 μmol, 50%) as a colorless oil: [α]²³_D(−) 9.9

(c 0.22, CHCl₃); IR (neat) 2956, 2932, 2874, 1701, 1515, 1457, 1250,

1074, 1007, 806, 730 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J =

6.9 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.48−7.54 (m, 1H), 7.48−7.55 (m,

3H), 6.87 (d, J = 8.4 Hz, 2H), 6.69 (t, J = 7.6 Hz, 1H), 5.84 (s, 1H), 5.05

(s, 1H), 4.96−5.00 (m, 1H), 4.87 (s, 1H), 4.56 (d, J = 10.5 Hz, 1H),

4.25−4.30 (m, 1H), 4.21 (d, J = 10.5 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 2H),

3.26 (dd, J = 9.6, 17.4 Hz, 1H), 3.20 (d, J = 8.1, 14.4 Hz, 1H), 2.99−3.04

(m, 1H), 2.96 (dd, J = 8.1, 15.0 Hz, 1H), 2.57 (dd, J = 2.8, 17.4 Hz, 1H),

2.21−2.30 (m, 4H), 1.89−1.92 (m, 1H), 1.84 (s, 3H), 1.79 (s, 3H),

1.45−1.78 (m, 10H), 1.42 (s, 3H), 1.30−1.36 (m, 1H), 1.25 (d, J = 5.6

Hz, 3H), 0.91−1.01 (m, 30H), 0.56−0.67 (m, 18H); ¹³C NMR (75

MHz, CDCl₃) δ 210.9, 167.5, 159.1, 147.7, 144.5, 142.4, 140.3, 133.4,

131.3, 129.9, 129.7, 129.2, 126.1, 126.0, 125.5, 115.4, 113.5, 88.5, 77.2,

71.7, 68.9, 65.6, 62.1, 59.6, 55.3, 49.6, 45.9, 45.7, 44.8, 41.1, 39.6, 31.7,

31.6, 30.9, 28.3, 26.2, 21.0, 19.9, 15.2, 12.6, 12.1, 7.3, 7.0, 6.9, 5.3, 5.1;

HRMS (ES+) calcd for C₆₄H₁₀₆NO₁₁Si₃Se (M + 1) 1228.6239, found

1228.6216.

Hydroxyl Epoxide 76. To a solution of (+)-DIPT (0.11 mL,

89 μmol, 0.8 M in CH₂Cl₂) were added CH₂Cl₂(0.30 mL) and 4 Å MS

(30 mg). The resulting mixture was cooled to −20 °C, and Ti(O-i-Pr)₄

(21.6 mg, 20.0 μL, 76 μmol) was added. After 30 min, TBHP (14.2 μL,

76 μmol, 5.5 M in decane) was added dropwise. After another 30 min,

a solution of alcohol 75 (13 mg, 13 μmol) in CH₂Cl₂(0.30 mL) was

added dropwise via cannula, and the reaction was allowed to warm to

0 °C. After 16 h, the reaction was cooled back to −20 °C, and a brine

solution of NaOH (0.5 mL, 1.0 M) was added. After 5 min, the reaction

was diluted with brine (0.5 mL) and CH₂Cl₂(0.5 mL) and warmed to rt.

Next, the mixture was extracted with CH₂Cl₂(3 × 15 mL) and the dried

(MgSO₄) extract concentrated in vacuo. The crude mixture was puriﬁed

by preparative TLC, eluting with 25% EtOAc/hexane, to give vinyl

epoxide 76 (7.0 mg, 7.0 μmol, 54%) as a colorless oil: [α]²³_D(+) 12.2

(c 0.36, CHCl₃); IR (neat) 3467, 3017, 2954, 2917, 2875, 2849, 2107,

1709, 1515, 1462, 1378, 1251, 1173, 1125, 1070, 1018, 835, 756, 667

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.8 Hz, 2H), 6.90 (d,

J = 8.8 Hz, 2H), 6.77 (t, J = 7.6 Hz, 1H), 5.80 (s, 1H), 5.06 (s, 1H), 4.95−

5.00 (m, 1H), 4.87 (s, 1H), 4.60 (d, J = 10.8 Hz, 1H), 4.22−4.30 (m,

1H), 4.21 (d, J = 10.8 Hz, 1H), 3.85 (s, 3H), 3.75−3.84 (m, 1H), 3.67−

3.74 (m, 2H), 3.22 (dd, J = 9.2, 18.0 Hz, 1H), 3.05−3.10 (m, 1H), 2.78−

2.81 (m, 1H), 2.54 (dd, J = 3.2, 18.0 Hz, 1H), 2.38 (br, 1H), 2.21−2.30

Allyl Epoxide 79. To a solution of selenide 78 (5.7 mg, 5.0 μmol) in

CH₂Cl₂(0.25 mL) at rt were added sequentially triethylamine (19 mg,

26.0 μL, 0.18 mmol), TPAP (16 mg, 45 μmol), and NMO (35 mg,

0.3 mmol). After 30 min, the reaction mixture was puriﬁed directly

by preparative TLC, eluting with 25% EtOAc/hexanes, to give vinyl

epoxide 79 (2.5 mg, 2.4 μmol, 48%) as a colorless oil: [α]²³−1.3

D

(c 0.15, CHCl₃); IR (neat) 3467, 3017, 2954, 2917, 2875, 2849, 2107,

1709, 1515, 1462, 1378, 1251, 1173, 1125, 1070, 1018, 835, 756, 667

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.34 (d, J = 8.4 Hz, 2H),

6.89 (d, J = 8.4 Hz, 2H), 6.73 (t, J = 7.6 Hz, 1H), 5.85−5.92 (m, 1H),

5.78 (s, 1H), 5.27 (dd, J = 8.0, 15.2 Hz, 1H), 5.01−5.04 (m, 2H), 4.85 (s,

1H), 4.57 (d, J = 10.4 Hz, 1H), 4.28−4.32 (m, 1H), 4.21 (d, J = 10.4 Hz,

1H), 3.85 (s, 3H), 3.70−3.74 (m, 2H), 3.25 (dd, J = 9.6, 17.2 Hz, 1H),

3.09 (dd, J = 2.0, 6.4 Hz, 1H), 2.90−2.94 (m, 1H), 2.54 (dd, J = 2.8, 17.2

Hz, 1H), 2.06−2.28 (m, 4H), 1.94 (d, J = 2.4, 10.8 Hz, 1H), 1.86 (s, 3H),

1.80−1.86 (m, 3H), 1.79 (s, 3H), 1.53−1.70 (m, 7H), 1.46 (s, 3H),

1.30−1.36 (m, 1H), 1.25 (d, J = 6.0 Hz, 3H), 0.90−1.01 (m, 27H), 0.86

(d, J = 6.0 Hz, 3H), 0.54−0.68 (m, 18H); ¹³C NMR (100 MHz, CDCl₃)

δ 211.0, 167.6, 159.1, 144.6, 142.4, 140.5, 134.3, 130.1, 129.8, 129.5,

128.7, 125.2, 115.3, 113.5, 88.4, 76.4, 71.7, 68.9, 65.7, 59.6, 58.5, 55.3,

49.4, 46.1, 45.6, 40.6, 40.2, 32.1, 30.9, 30.5, 29.7, 28.0, 27.8, 20.4, 19.8,

V

dx.doi.org/10.1021/jo3026077 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

15.2, 13.0, 12.5, 7.3, 7.0, 6.9, 6.8, 5.2, 5.1; HRMS (ES+) calcd for

C₅₈H₁₀₀O₉Si₃Na (M + Na) 1047.6573, found 1047.6664.

NMR (100 MHz, CDCl₃) δ 203.1, 144.7, 141.0, 126.0, 114.9, 76.9, 61.5,

54.2, 46.0, 39.9, 28.5, 27.8, 26.0, 19.5, 18.3, 14.7, 7.1, 6.7, −5.3; HRMS (EI⁺)

calcd for C₂₆H₅₂O₃Si₂(M⁺) 468.3455, found 468.3448.

TES Ether SI-21. To a stirred solution of diol 65 (470 mg, 1.32 mmol)

in DCM/TEA (6 mL, 1:1) was added freshly distilled TESOTf (1.05 g, 0.89

mL, 3.96 mmol) at −78 °C. After 30 min, the reaction was quenched with

satd aq NaHCO₃(1 mL) and extracted with ether (3 × 20 mL).

The dried extract (MgSO₄) was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 2−5% EtOAc/hexanes, to give

Aldol Adduct SI-24. To a stirred solution of SI-23 (1.60 g,

0.15 mmol) in CH₂Cl₂(11.2 mL) at −60 °C were added sequentially

Et₃N (0.44 g, 0.60 mL, 4.33 mmol) and Bu₂BOTf (1.19 g, 1.08 mL,

4.33 mmol). After 3 h, the resulted solution was warmed to 0 °C for

30 min and then cooled back to −60 °C. A solution of aldehyde 37⁸

(1.12 g, 4.86 mmol) in DCM (4.8 mL) was transferred to the reaction

mixture via cannula. After 2 h, the reaction was allowed to warm to 0 °C.

After another 20 min, the reaction was quenched by addition of pH 7

phosphate buﬀer (20 mL) followed by MeOH (15 mL) and 30% H₂O₂

(4 mL). After 1 h, the reaction mixture was extracted with EtOAc

(4 × 35 mL). The dried (MgSO₄) extract was concentrated in vacuo

and puriﬁed by chromatography over silica gel, eluting with 15−20%

EtOAc/hexanes, to give SI-24 (1.58 g, 2.57 mmol, 62%) as a colorless

oil: [α]²³_D= −9.2 (c 0.77, CHCl₃); IR (neat) 3493, 2957, 2876, 1781,

SI-21 (732 mg, 1.25 mmol, 95%) as a colorless oil: [α]²³= −21.3°

D

(c 1.37, CHCl₃); IR (neat) 2954, 2929, 2876, 1460, 1254, 1093, 1007, 835,

741 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 5.88 (s, 1H), 4.99 (s, 1H), 4.80 (s,

1H), 3.61−3.71 (m, 3H), 3.47 (dt, J = 15.6, 5.4 Hz, 1H), 2.15 (dd, J = 13.5,

5.4 Hz, 1H), 1.80−1.99 (m, 5H), 1.77 (d, J = 0.9 Hz, 3H), 1.54−1.66 (m,

1H), 0.88−1.00 (m, 27H), 0.84 (d, J = 6.3 Hz, 3H), 0.55−0.66 (m, 12H),

0.063 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 145.2, 142.0, 124.6, 114.1,

77.2, 61.7, 59.3, 46.2, 44.5, 40.0, 28.7, 26, 19.6, 18.4, 14.7, 7.2, 7.0, 6.9, 6.8, 4.4,

−5.3; HRMS (EI⁺) calcd for C₃₂H₆₈O₃Si₃(M⁺) 584.4476, found 584.4500.

1709, 1593, 1517, 1455, 1390, 1265, 1240, 1159, 1052, 1028, 746 cm⁻¹

;

¹H NMR (400 MHz) δ 7.23−7.38 (m, 5H), 6.83−7.03 (m, 3H), 5.36

(d, J = 2.0 Hz, 1H), 4.63−4.71 (m, 2H), 4.51 (d, J = 10.8 Hz, 1H),

4.21−4.29 (m, 2H), 3.93 (s, 3H), 3.84−3.90 (m, 1H), 3.88 (s, 3H),

3.62−3.66 (m, 1H), 3.32 (dd, J = 13.6, 3.6 Hz, 1H), 2.77 (dd, J = 13.6, 10.0

Hz, 1H), 2.32(d, J = 10.0 Hz, 1H), 1.78−1.80 (m, 1H), 1.58−1.64 (m, 1H),

1.15 (d, J = 6.0 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.98 (t, J = 8.0 Hz, 9H),

0.62 (q, J = 8.0 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 177.2, 153.2,

149.1, 149.0, 135.2, 129.5, 129.4, 129.0, 127.4, 121.4, 112.1, 110.9, 78.1,

76.1, 66.9, 55.9, 55.7, 42.8, 37.7, 34.1, 23.2, 15.7, 6.9, 4.9; HRMS (ES⁺) calcd

for C₃₃H₄₉NO₈SiNa (M + Na) 638.3125, found 638.3155.

Alcohol SI-22. TES ether SI-21 (300 mg, 0.51 mmol) was dissolved

in a stirred solution of HOAc/THF/H₂O (8 mL, 8:8:1) at 0 °C. After

1.5 h, the reaction was then quenched with solid NaHCO₃and extracted

with ether (3 × 20 mL). The dried extract (MgSO₄) was concentrated in

vacuo and puriﬁed by chromatography over silica gel, eluting with 10%

EtOAc/hexanes, to give alcohol SI-22 (241 mg, 0.51 mmol, 99%) as a

colorless oil: [α]²³= −15.5° (c 0.64, CHCl₃); IR (neat) 3437, 2954,

D

1

2928, 2876, 1461, 1254, 1099, 1008, 835 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 6.02 (s, 1H), 5.04 (s, 1H), 4.85 (s, 1H), 3.63−3.73(m, 4H),

2.79 (t, J = 5.6 Hz, 1H), 2.17 (dd, J = 13.6, 5.6 Hz, 1H), 1.88−1.97 (m,

3H), 1.74−1.83 (m, 1H), 1.79 (d, J = 1.2 Hz, 3H), 1.59−1.68 (m, 1H),

1.47 (s, 3H), 1.28−1.40 (m, 1H), 0.99−1.03 (t, J = 7.6 Hz, 9H), 0.92 (s,

9H), 0.88 (d, J = 6.4 Hz, 3H), 0.69 (q, J = 7.2 Hz, 6H), 0.078 (s, 6H); ¹³C

NMR (100 MHz, CDCl₃) δ 145.0, 141.4, 125.6, 114.6, 80.0, 61.6, 60.1,

46.1, 42.8, 39.9, 29.7, 28.6, 27.6, 26.0, 19.5, 18.4, 14.9, 7.2, 6.9, 6.8, −5.3;

HRMS (EI⁺) calcd for C₂₆H₅₄O₃Si₂(M⁺) 470.3611, found 470.3604.

TES Ether SI-25. To a stirred solution of adol adduct SI-24 (500 mg,

0.81 mmol) in DCM (3.32 mL) at 0 °C were added sequentially

2,6-lutidine (184 mg, 0.20 mL, 1.72 mmol) and TESOTf (287 mg,

0.25 mL, 1.09 mmol). After 1 h, the reaction was quenched with satd

aq NH₄Cl (10 mL) and extracted with Et₂O (3 × 30 mL). The dried

(MgSO₄) extract was concentrated in vacuo and puriﬁed by chromatography

over silica gel, eluting with 15% EtOAc/hexanes, to give SI-25 (570 mg,

0.78 mmol, 96%) as a colorless oil: [α]²³_D= −40.7 (c 0.42, CHCl₃);

IR (neat) 2955, 2911, 2876, 1784, 1702, 1517, 1456, 1239, 1084, 740

1

cm⁻¹; H NMR (300 MHz) δ 7.17−7.32 (m,H), 6.80−7.00 (m, 3H),

Aldehyde 82. To a stirred solution of alcohol SI-22 (1.29 g,

2.73 mmol) in DCM (40 mL, 1:1) were added sequentially DMP

(2.17 g, 5.12 mmol) and NaHCO₃(1.68 g, 20.0 mmol) at rt. After

30 min, the reaction was quenched with satd aq NaHCO₃(10 mL) and

extracted with ether (3 × 40 mL). The dried extract (MgSO₄) was

concentrated in vacuo and puriﬁed by chromatography over silica

gel, eluting with 5% EtOAc/hexanes, to give aldehyde 82 (1.17 g,

2.49 mmol, 91%) as a colorless oil: [α]²³_D= −12.5 (c 0.56, CHCl₃); IR

(neat) 2955, 2929, 2877, 1725, 1255, 1099, 1007, 836, 726 cm⁻¹; ¹H

NMR (300 MHz, CDCl₃) δ 9.69 (t, J = 3.3 Hz, 1H), 6.03 (s, 1H), 5.03

(s, 1H), 4.83 (s, 1H), 3.61−3.68(m, 2H), 2.64 (dd, J = 15.0, 3.0 Hz,

1H), 2.45 (dd, J = 15.0, 3.0 Hz, 1H), 2.15 (dd, J = 13.5, 6.0 Hz, 1H),

1.85−1.92 (m, 1H), 1.83 (d, J = 1.2 Hz, 3H), 1.54−1.64 (m, 1H),

1.49 (s, 3H), 1.25−1.35 (m, 2H), 0.95−1.00 (t, J = 7.7 Hz, 9H), 0.91

(s, 9H), 0.85 (d, J = 6.5Hz, 3H), 0.65 (q, J = 7.8 Hz, 6H), 0.061 (s, 6H); ¹³C

5.28 (d, J = 6.0 Hz, 1H), 4.71 (d, J = 11.7 Hz, 1H), 4.54 (d, J = 11.7 Hz, 2H),

4.47−4.49 (m, 1H), 4.00−4.12 (m, 3H), 3.90 (s, 3H), 3.84 (s, 3H), 3.78−

3.82 (m, 1H), 3.14 (dd, J = 3.0, 13.2 Hz, 1H), 2.40 (dd, J = 10.5, 13.5 Hz,

1H), 1.42−1.56 (m, 3H), 1.11 (d, J = 5.7 Hz, 3H), 0.89−0.97 (m, 21H),

0.55−0.63 (m, 12H); ¹³C NMR (100 MHz, CDCl₃) δ 171.9, 152.9, 148.7,

148.8, 135.3, 130.3, 129.3, 129.0, 127.3, 121.1, 111.9, 110.7, 73.4, 67.2, 66.4,

56.0, 55.9, 55.8, 44.4, 37.4, 33.5, 23.7, 14.8, 7.1, 6.9, 5.4, 5.3, 5.2, 5.0; HRMS

(ES⁺) calcd for C₃₉H₆₃NO₈Si₂Na (M + Na) 752.3990, found 752.3992.

W

dx.doi.org/10.1021/jo3026077 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

Thiol Ester SI-26. To a stirred solution of EtSH (90 mg, 0.107 mL,

1.45 mmol) in THF (12.6 mL) at 0 °C was added n-BuLi (0.51 mL, 1.27

mmol, 2.5 M in hexanes). After 1 h, a solution of SI-25 (610 mg, 0.83

mmol) in THF (2.7 mL) was added dropwise via cannula. After another

1 h, the reaction was quenched with satd aq NH₄Cl (10 mL) and

extracted with Et₂O (3 × 30 mL). The dried (MgSO₄) extract was

concentrated in vacuo and puriﬁed by chromatography over silica gel,

eluting with 5−8% EtOAc/hexanes, to give SI-26 (470 mg, 0.76 mmol,

92%) as a colorless oil: [α]²³_D= +42.0 (c 0.39, CHCl₃); IR (neat) 2955,

2911, 2876, 1683, 1517, 1458, 1419, 1378, 1266, 1240, 1161, 1079,

1032, 811, 740 cm⁻¹; ¹H NMR (400 MHz) δ 7.04 (dd, J = 1.6 Hz, 1H),

6.94 (dd, J = 1.6, 8.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.63 (d, J = 10.8

Hz, 1H), 4.43 (d, J = 10.8 Hz, 1H), 3.94 (s, 3H), 3.92−3.93 (m, 4H),

3.81−3.86 (m, 2H), 2.91 (q, J = 7.6 Hz, 2H), 1.45−1.57 (m, 3H), 1.30

(t, J = 7.2 Hz, 3H), 1.14 (d, J = 6.0 Hz, 3H), 0.90−0.98 (m, 21H), 0.53−

0.62 (m, 12H); ¹³C NMR (100 MHz, CDCl₃) δ 202.2, 148.8, 148.6,

129.9, 120.6, 110.6, 110.7, 88.2, 72.9, 66.9, 55.9, 55.8, 44.9, 32.7, 23.4,

22.5, 14.6, 13.6, 7.0, 6.9, 5.3, 5.2, 5.0; HRMS (ES⁺) calcd for

C₃₁H₅₈O₆Si₂SNa (M + Na) 637.3390, found 637.3407.

EtOAc/hexanes, to sequentially give aldol adduct SI-27 (10 mg, 0.0096

mmol, 18%) and 83 (39 mg, 0.0375 mmol, 71%) and as colorless oils.

83: [α]²³_D= +9.1 (c 0.58, CHCl₃); IR (neat) 3503, 2955, 2934, 2876,

1

1715, 1517, 1463, 1265, 1240, 1095, 1007, 741 cm⁻¹; H NMR (400

MHz, CDCl₃) δ 6.83−6.97 (m, 3H), 5.90 (s, 1H), 5.05 (s, 1H), 4.85 (s,

1H), 4.53 (d, J = 11.2 Hz, 1H), 4.44−4.50 (m, 1H), 4.39(d, J = 10.8 Hz,

1H), 3.91 (s, 6H), 3.76−3.83 (m, 3H), 3.66−3.70 (m, 2H), 3.05 (dd, J =

17.6, 6.8 Hz, 1H), 2.38 (dd, J = 17.6, 5.6 Hz, 1H), 2.19 (dd, J = 13.5, 4.8

Hz, 1H), 1.80−1.91 (m, 1H), 1.84 (s, 3H), 1.48−1.68 (m, 4H), 1.57 (s,

3H), 1.20−1.42 (m, 4H), 1.10 (d, J = 6.0 Hz, 3H), 0.86−1.00 (m, 42H),

0.57−0.66 (m, 18H), 0.08 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ

211.0, 148.8, 148.6, 144.6, 142.9, 130.1, 125.2, 120.7, 114.9, 111.5, 110.7,

88.3, 79.5, 72.6, 66.9, 64.8, 61.4, 55.9, 55.8, 48.0, 46.7, 46.0, 44.8, 39.9,

33.1, 28.4, 23.3, 19.5, 14.7, 13.5, 7.1, 7.0, 6.9, 6.5, 5.3, 5.0, −5.2; HRMS

(ES⁺) calcd for C₅₆H₁₀₇O₉Si₄(M + H) 1035.6992, found 1035.7047.

Enone 93. To a stirred slurry of NaH (36 mg, 0.90 mmol, 60% w/w

in mineral oil) in DME (2 mL) was added phosphonate 92 (138 mg,

0.83 mmol) at rt. After 1 h, a solution of aldehyde 37 (160 mg,

0.69 mmol) in DME (2 mL) was added via cannula. After another 6 h,

the reaction was quenched with satd aq NH₄Cl (2 mL) and extracted

with Et₂O (4 × 10 mL). The dried extract (MgSO₄) was concentrated in

vacuo and puriﬁed by chromatography over silica gel, eluting with 5%

EtOAc/hexanes, to give enone 93 (142 mg, 0.52 mmol, 76%) as a colorless

oil: [α]²³_D= −46.0° (c 1.47, CHCl₃); IR (neat) 2958, 2877, 1700, 1678,

1627, 1458, 1360, 1252, 1139, 1055, 984, 745 cm⁻¹; ¹H NMR (300 MHz,

CDCl₃) δ 6.76 (dd, J = 15.9, 7.8 Hz, 1H), 6.09 (d, J = 15.9 Hz, 1H), 3.86−

3.79 (m, 1H), 2.58−2.53 (m, 1H), 2.26 (s, 3H), 1.41−1.55 (m, 2H), 1.18

(d, J = 6.0 Hz, 3H), 1.09 (d, J = 6.9Hz, 3H), 0.97(t, J = 7.8 Hz, 9H), 0.64 (q,

J = 7.5 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 198.8, 153.5, 129.6, 66.4,

46.3, 33.4, 27.0, 24.3, 20.3, 6.9, 5.2, 5.0; HRMS (EI⁺) calcd for C₁₅H₃₀O₂Si

(M⁺) 270.2015, found 270.2008.

Methyl Ketone 81. To a stirred slurry of CuI (859 mg, 4.51 mmol) in

Et₂O (8.3 mL) at 0 °C was added MeLi (5.6 mL, 9.6 mmol, 1.6 M in Et₂O).

After 15 min, the colorless solution was cooled to −50 °C, and a solution of

SI-26 (450 mg, 0.75 mmol) in Et₂O (4.2 mL) was transferred into the

reaction mixture dropwise via cannula. After 2 h, the reaction was quenched

with satd aq NH₄Cl (10 mL) at −50 °C, warmed to rt, and extracted with

Et₂O (3 × 30 mL). The dried (MgSO₄) extract was concentrated in vacuo

and puriﬁed by chromatography over silica gel, eluting with 2−4% EtOAc/

hexanes, to give 81 (296 mg, 0.52 mmol, 71%) as a colorless oil: [α]²³

=

D

+22.6 (c 0.23, CHCl₃); IR (neat) 2955, 2911, 2876, 1716, 1517, 1457, 1267,

1240, 1082, 1031, 1007, 741 cm⁻¹; ¹H NMR (400 MHz) δ 6.82−6.90 (m,

3H), 4.50 (dd, J = 11.4, 15.0 Hz, 2H), 3.90 (s, 6H), 3.80−3.85(m, 2H), 3.76

(d, J = 6.3 Hz, 1H), 2.13 (s, 3H), 1.50−1.52 (m, 3H), 1.13 (d, J = 6.0 Hz,

3H), 0.88−1.00 (m, 21H), 0.57−0.64 (m, 12H); ¹³C NMR (100 MHz,

CDCl₃) δ 210.6, 148.8, 129.9, 120.7, 111.4, 110.8, 88.5, 72.9, 67.0, 55.9,

55.8, 44.5, 33.1, 27.0, 23.5, 14.0, 7.0, 6.9, 5.3, 5.0; HRMS (ES⁺) calcd for

C₃₀H₅₆O₆Si₂Na (M + Na) 591.3513, found 591.3527.

Diol 94. To a stirred solution of enone 93 (142 mg, 0.52 mmol) in

t-BuOH/H₂O (5 mL, 1:1) at 0 °C were added sequentially AD-mix-α

(0.735 g), NaHCO₃(132 mg, 1.57 mmol), MeSO₂NH₂(50.6 mg, 0.53

mmol), and K₂OsO₂(OH)₄(1.9 mg, 0.005 mmol). After 8 h, the reaction

was quenched with satd aq Na₂SO₃(8 mL) and extracted with EtOAc (4 ×

10 mL). The dried extract (MgSO₄) was concentrated

in vacuo and puriﬁed by chromatography over silica gel, eluting with 15−

40% EtOAc/hexanes, to give diol 94 (122 mg, 0.40 mmol, 77%) as a

colorless oil: [α]²³_D= −29.2 (c 1.5, CHCl₃); IR (neat) 3456, 2957, 2877,

1

1717, 1380, 1238, 1132, 1048, 1011, 744 cm⁻¹; H NMR (300 MHz,

CDCl₃) δ 4.28 (d, J = 3.6 Hz, 1H), 4.04−3.99 (m, 1H), 3.72−3.78 (m, 1H

and OH), 2.41 (d, J = 10.4 Hz, 1H), 2.30 (s, 3H), 1.89−1.96 (m, 1H),

1.71−1.77 (m, 1H), 1.40−1.47 (m, 1H), 1.22 (d, J = 6.0 Hz, 3H), 1.10 (d,

J = 6.8 Hz, 3H), 1.00 (t, J = 7.8 Hz, 9H), 0.68 (q, J = 7.9 Hz, 6H); ¹³C NMR

(100 MHz, CDCl₃) δ 208.9, 77.7, 75.2, 66.9, 42.8, 34.0, 25.3, 23.1, 16.4, 6.9,

4.9; HRMS (ES⁺) calcd for C₁₅H₃₂O₄SiNa (M + Na) 327.1968, found

327.1950.

Aldol Adduct 83. To a stirred solution of methyl ketone 81 (30 mg,

0.0527 mmol) in Et₂O (0.5 mL) at −78 °C was added LDA⁵⁴(64 μL,

0.064 mmol, 1 M in THF). After 15 min, a precooled (−78 °C) solution

of aldehyde 82 (50 mg, 0.105 mmol) in THF (0.5 mL) was added via

cannula in one portion. After another 0.5 h, the reaction was quenched

with satd aq NH₄Cl (2 mL) at −78 °C, warmed to rt, and extracted with

ether (3 × 10 mL). The dried extract (MgSO₄) was concentrated in

vacuo and puriﬁed by chromatography over silica gel, eluting with 6−8%

X

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TES Ether 95. To a stirred solution of diol 94 (800 mg, 2.63 mmol)

in CH₂Cl₂(10 mL) at −78 °C were added sequentially 2,6-lutidine

(1.41 g, 1.53 mL, 13.1 mmol) and TESOTf (1.74 g, 1.49 mL, 6.58

mmol). After 30 min, the reaction was quenched with satd aq NH₄Cl

(10 mL) and extracted with Et₂O (4 × 25 mL). The dried extract

(MgSO₄) was concentrated in vacuo and puriﬁed by chromatography

over silica gel, eluting with 10% EtOAc/hexanes, to give TES ether 95

1.24 mmol). After 4 h, the reaction was quenched with satd aq NH₄Cl

(10 mL) and extracted with EtOAc (4 × 20 mL). The dried extract

(MgSO₄) was concentrated in vacuo and puriﬁed by chromatography

over silica gel, eluting with 15% EtOAc/hexanes, to give alcohol SI-28

(369 mg, 0.88 mmol, 72%) as a colorless oil: [α]²³= −7.6 (c 1.2,

D

CHCl₃); IR (neat) 3434, 2957, 2878, 1716, 1459, 1415, 1239, 1005, 739

cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 4.17 (d, J = 5.4 Hz, 1H), 3.81 (m,

1H), 3.69 (dd, J = 5.4, 3.9 Hz, 1H), 2.22 (s, 3H), 1.83 (m, 1H), 1.61−

1.69 (m, 1H), 1.24−1.30 (m, 1H), 1.20 (d, J = 6.0 Hz, 3H), 0.94−1.04

(m, 18H), 0.87 (d, J = 6.6 Hz, 3H), 0.58−0.71 (m, 12H); ¹³C NMR (100

MHz, CDCl₃) δ 210.1, 81.5, 78.1, 66.2, 43.8, 32.9, 27.6, 24.4, 15.2, 7.0,

6.8, 5.2, 4.8; HRMS (ES⁺) calcd for C₂₁H₄₇O₄Si₂(M + H) 419.3013,

found 419.2993.

(1.29 g, 2.42 mmol, 92%) as a colorless oil: [α]²³= −0.83° (c 1.2,

D

CHCl₃); IR (neat) 2957, 2878, 1716, 1458, 1238, 1005 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 4.07 (d, J = 6.0 Hz, 1H), 3.78−3.85 (m, 1H), 3.70

(dd, J = 5.9, 2.6 Hz, 1H), 2.20 (s, 3H), 1.60−1.64 (m, 1H), 1.45−1.51

(m, 2H), 1.13 (d, J = 6.0 Hz, 3H), 0.94−1.00 (m, 27H), 0.83 (d, J = 6.6

Hz, 3H), 0.55−0.70 (m, 18H); ¹³C NMR (75 MHz, CDCl₃) δ 210.0,

81.5, 78.6, 67.1, 45.4, 32.2, 27.3, 23.1, 14.0, 7.0, 6.84, 6.79, 5.2, 4.9, 4.8;

HRMS (ES⁺) calcd for C₂₇H₆₀O₄Si₃Na (M + Na) 555.3697, found

555.3683.

TMS Ether 98. To a stirred solution of alcohol SI-28 (1.90 g,

4.54 mmol) in CH₂Cl₂(25 mL) at −78 °C were added sequentially

2,6-lutidine (1.45 g, 1.58 mL, 13.5 mmol) and TMSOTf (1.51 g,

1.23 mL, 6.81 mmol). After 30 min, the reaction was quenched with satd

aq NH₄Cl (10 mL) and extracted with Et₂O (4 × 20 mL). The dried

extract (MgSO₄) was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 10% EtOAc/hexanes, to

Alcohol 96. TES ether 95 (5.60 g, 10.5 mmol) was dissolved in a

stirred solution of HOAc/THF/H₂O (107 mL, 8:8:1) at 0 °C. After

12 h, the reaction was quenched with solid NaHCO₃, ﬁltered over

Celite, and extracted with ether (4 × 100 mL). The dried extract

(MgSO₄) was concentrated in vacuo and puriﬁed by chromatography

over silica gel, eluting with 10% EtOAc/hexanes, to give alcohol 96

give TMS ether 98 (2.12 g, 4.32 mmol, 95%) as a colorless oil: [α]²³

=

D

+14.4 (c 2.2, CHCl₃); IR (neat) 2957, 2878, 1716, 1459, 1415, 1124,

1006, 841, 741 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 4.03 (d, J = 6.3 Hz,

1H), 3.79−3.85 (m, 1H), 3.71 (dd, J = 6.3, 2.4 Hz, 1H), 2.19 (s, 3H),

1.73−1.79 (m, 1H), 1.45−1.54 (m, 1H), 1.23−1.32 (m, 1H), 1.16 (d, J =

6.0 Hz, 3H), 0.95−1.03 (m, 18H), 0.83 (d, J = 6.6 Hz, 3H), 0.58−0.70

(m, 12H); ¹³C NMR (75 MHz, CDCl₃) δ 210.2, 81.8, 78.6, 65.9, 45.3,

31.3, 26.8, 24.7, 13.2, 7.0, 6.8, 5.3, 4.8, 0.3; HRMS (ES⁺) calcd for

C₂₄H₅₄O₄Si₃Na (M + Na) 513.3224, found 513.3204.

(3.90 g, 9.31 mmol, 89%) as a colorless oil: [α]²³= −30.5 (c 1.45,

D

CHCl₃); IR (neat) 3446, 2958, 2878, 1716, 1458, 1239, 1005, 739 cm⁻¹;

¹H NMR (300 MHz, CDCl₃) δ 4.18 (d, J = 5.6 Hz, 1H), 3.86−3.88 (m,

2H), 2.24 (s, 3H), 1.80−1.90 (m, 1H), 1.41−1.55 (m, 2H), 1.20 (d, J =

6.0 Hz, 3H), 0.97−1.05 (m, 18H), 0.87 (d, J = 6.8 Hz, 3H), 0.61−0.73

(m, 12H); ¹³C NMR (75 MHz, CDCl₃) δ 209.3, 81.4, 76.4, 65.6, 43.7,

31.6, 27.8, 23.6, 15.4, 7.0, 6.8, 5.2, 4.8, 4.7; HRMS (ES⁺) calcd for

C₂₁H₄₆O₄Si₂Na (M + Na) 441.2832, found 441.2836.

PNB Ester 97. To a stirred solution of alcohol 96 (600 mg,

1.43 mmol) in THF (15 mL) at 0 °C were added sequentially PPh₃

(1.50 g, 5.72 mmol), 4-nitrobenzoic acid (0.96 g, 5.74 mmol), and

DEAD (0.99 g, 0.90 mL, 5.70 mmol). After 1 h, the reaction mixture

was concentrated in vacuo and puriﬁed by chromatography over silica

gel, eluting with 1−3% EtOAc/hexanes, to give ester 97 (670 mg,

1.18 mmol, 82%) as a colorless oil: [α]²³_D= +13.6 (c 1.08, CHCl₃); IR

(neat) 2956, 2878, 1723, 1530, 1319, 1275, 1014, 721 cm⁻¹; ¹H NMR

(300 MHz, CDCl₃) δ 8.31 (d, J = 9.0 Hz, 2H), 8.23 (d, J = 9.0 Hz, 2H),

5.26 (m, 1H), 4.17 (d, J = 4.8 Hz, 1H), 3.69 (t, J = 4.8 Hz, 1H), 2.18 (s,

3H), 2.02−2.12 (m, 1H), 1.76 (m, 1H), 1.45−1.49 (m, 1H), 1.38 (d, J =

6.1 Hz, 3H), 0.93−1.02 (m, 18H), 0.90 (d, J = 6.6 Hz, 3H), 0.56−0.70

(m, 12H); ¹³C NMR (100 MHz, CDCl₃) δ 209.3, 164.3, 150.4, 136.1,

130.7, 123.4, 81.5, 78.2, 70.8, 40.2, 32.4, 27.9, 20.9, 14.8, 7.0, 6.8, 5.1, 4.8;

HRMS (ES⁺) calcd for C₂₈H₄₉NO₇Si₂Na (M + Na) 590.2945, found

590.2926.

Aldol Adducts 100 and 103. To a stirred solution of methyl ketone

98 (312 mg, 0.64 mmol) in THF (5 mL) at −78 °C was added LDA²

(0.765 mL, 1 M in THF). After 15 min, TMEDA (133 mg, 0.172 mL,

1.14 mmol) was added. After 5 min, the reaction was warmed up to

−40 °C, followed by the addition of a precooled (−40 °C) solution of

aldehyde 82 (200 mg, 0.43 mmol) in THF (5 mL) via cannula in one

portion. After another 0.5 h, the reaction was quenched with satd aq

NH₄Cl (10 mL) −78 °C, warmed to rt, and extracted with ether (4 ×

20 mL). The dried extract (MgSO₄) was concentrated in vacuo and

puriﬁed by chromatography over silica gel, eluting with 1−1.5% EtOAc/

hexanes, to give aldol adduct 100 (142 mg, 0.15 mmol, 35%) and 103

(114 mg, 0.12 mmol, 28%) as colorless oil. 100: [α]²³_D= −12.0 (c 1.3,

CHCl₃); IR (neat) 3511, 2955, 2929, 2877, 1715, 1460, 1413, 1250,

1092, 1006, 838, 742 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 5.89 (s, 1H),

5.02 (s, 1H), 4.83 (s, 1H), 4.33 (m, 1H), 4.10 (d, J = 5.7 Hz, 1H), 3.82

Alcohol SI-28. To a stirred solution of ester 97 (700 mg, 1.23 mmol)

in MeOH (20 mL) at 0 °C was added Ba(OH)₂·8H₂O (390 mg,

Y

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(m, 1H), 3.74 (s, 1H), 3.64−3.72 (m, 3H), 2.96 (dd, J = 17.7, 6.2 Hz,

1H), 2.60 (dd, J = 18.1, 6.4 Hz, 1H), 2.18 (dd, J = 12.8, 4.0 Hz, 1H),

1.81−1.90 (m, 2H), 1.84 (s, 3H), 1.47−1.67 (m, 4H), 1.56 (s, 3H),

1.22−1.38 (m, 3H), 1.15 (d, J = 6.0 Hz, 3H), 0.92−1.03 (m, 36H), 0.87

(d, J = 6.4 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H), 0.58−0.70 (m, 18H), 0.10

(s, 9H), 0.06 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 210.7, 144.7,

125.1, 114.7, 81.1, 79.4, 78.4, 65.9, 65.1, 61.5, 48.2, 47.2, 46.0, 45.0, 39.9,

31.1, 28.5,26.2, 26.0, 24.7, 19.5, 18.3, 14.7, 13.8, 7.2, 7.1, 6.9, 6.6, 5.3, 4.9,

0.4, −5.2; HRMS (ES⁺) calcd for C₅₀H₁₀₆O₇Si₅Na (M + Na) 981.6683,

found 981.6646.

MTPA Esters. To a solution of 100 (5 mg, 0.005 mmol) in CH₂Cl₂

(0.5 mL) were added sequentially DMAP (6.4 mg, 0.052 mmol) and

(R)- or (S)-(+)-α-methoxy-α-triﬂuoromethylphenylacetyl chloride

(6.6 mg, 4.9 μL, 0.026 mmol). After 10 min, the solution was evaporated,

and the residue was loaded directly onto silica gel and puriﬁed by

chromatography, eluting with 2 - 10% EtOAc/hexanes, to give product

(S)- or (R)- MTPA esters (52−61%) as colorless oils. ¹H NMR diﬀerence

in ppm [(S)-Mosher ester − (R)-Mosher ester, CDCl₃, CDCl₃, 300 MHz

NMR] H₁₉= 2.847 − 2.834 = +0.013, H₂₁: 3.996 − 3.961 = +0.035,

H₂₂: 3.686 − 3.678 = +0.008, H₂₅: 3.848 − 3.818 = +0.030, H_31’: 0.881 −

0.876 = +0.005, H₂₉: 1.888 − 1.895 = −0.007, H₁₄: 5.723 − 5.824 =

−0.101, H₂₈: 4.905 − 4.925 = −0.020, H₁₂: 2.319 − 2.334 = −0.015, H₂₇:

1.130 − 1.137 = −0.007.

¹H NMR (300 MHz, CDCl₃) δ 5.89 (s, 1H), 5.02 (s, 1H), 4.83 (s, 1H),

4.38−4.27 (m, 1H), 4.06−4.10 (m, 3H), 3.86−3.75 (m, 1H), 3.72−3.68

(m, 1H), 3.66 (s, 1H, OH), 2.96 (dd, J = 17.9, 6.2 Hz, 1H), 2.59 (dd, J =

18.0, 6.1 Hz, 1H), 2.15 (dd, J = 13.2, 5.7 Hz, 1H), 2.04 (s, 3H), 1.94−

1.76 (m, 4H), 1.81 (s, 3H), 1.70−1.63 (m, 2H), 1.54 (s, 3H), 1.48−1.38

(m, 2H), 1.27−1.22 (m, 1H), 1.13 (d, J = 5.9 Hz, 3H), 1.02−0.93 (m,

27H), 0.89 (d, J = 6.3 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H), 0.59−0.69

(m, 18H), 0.09 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 210.8, 171.1,

144.3, 143.3, 124.8, 115.0, 81.0, 79.3, 78.4, 65.9, 65.0, 62.9, 48.2, 47.2,

45.8, 45.0, 35.3, 31.0, 28.7, 26.3, 24.6, 21.0, 19.3, 14.7, 13.8, 7.1, 7.0,

6.8, 6.6, 5.2, 4.9, 0.3; HRMS (ES⁺) calcd for C₄₆H₉₄O₈Si₄Na (M +

Na) 909.5924, found 909.5895. 104: [α]²³= +1.76 (c 1.25,

D

CHCl₃); IR (neat) 3511, 2956, 2913, 2877, 1743, 1718, 1458, 1369,

1249, 1119, 1088, 1011, 841, 742 cm⁻^{1 1}H NMR (400 MHz,

;

CDCl₃) δ 6.06 (s, 1H), 5.03 (s, 1H), 4.88 (s, 1H), 4.17−4.06 (m,

4H), 3.88 (s, 1H, OH), 3.88−3.81 (m, 1H), 3.73−3.69 (m, 1H),

2.66−2.78 (m, 2H), 2.17 (dd, J = 13.5, 6.0 Hz, 1H), 2.05 (s, 3H),

1.97−1.93 (m, 1H), 1.85−1.78 (m, 1H), 1.82(s, 3H), 1.74−1.70 (m,

1H), 1.62−1.14 (m, 4H), 1.44 (s, 3H), 1.28−1.20 (m, 2H), 1.14 (d, J = 5.8

Hz, 3H), 1.02−0.94 (m, 27H), 0.91 (d, J = 6.2 Hz, 3H), 0.78 (d, J = 6.6 Hz,

3H), 0.72−0.57 (m, 18H); ¹³C NMR (100 MHz, CDCl₃) δ 210.5, 171.1,

144.5, 140.8, 125.4, 114.8, 81.3, 80.7, 78.4, 66.0, 65.7, 63.0, 47.1, 45.9, 45.0,

35.2, 31.0, 29.7, 28.7, 28.2, 24.6, 21.0, 19.4, 14.9, 13.6, 7.1, 7.0, 6.9, 6.8, 6.6, 5.2,

4.8, 0.3; HRMS (ES⁺) calcd for C₄₆H₉₄O₈Si₄Na (M + Na) 909.5924, found

909.5948.

TES Ether SI-29. To a stirred solution of aldol adduct 101 (295 mg,

0.332 mmol) in CH₂Cl₂(10 mL) at rt were added sequentially DMAP

(608 mg, 4.98 mmol) and TESCl (375 mg, 0.418 mL, 2.49 mmol).

After 3 h, the reaction mixture was concentrated in vacuo and puriﬁed

by chromatography over silica gel, eluting with 2% EtOAc/hexanes, to

give TES ether SI-29 (290 mg, 0.289 mmol, 87%) as a colorless oil:

[α]²³= −31.4 (c 0.85, CHCl₃); IR (neat) 2955, 2913, 2877, 1745,

D

1

1718, 1459, 1368, 1249, 1127, 1086, 1007, 841, 742 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 5.78 (s, 1H), 5.03 (s, 1H), 4.92 (s, 1H), 4.20−

4.08 (m, 3H), 4.04 (d, J = 5.7 Hz, 1H), 3.84−3.81 (m, 1H), 3.72−3.68

(m, 1H), 2.86 (dd, J = 18.0, 5.8 Hz, 1H), 2.72 (dd, J = 17.4, 7.2 Hz,

1H), 2.17 (dd, J = 13.8, 6.0 Hz, 1H), 2.05 (s, 3H), 1.93−1.64 (m, 5H), 1.84

(s, 3H), 1.54−1.39 (m, 3H), 1.45 (s, 3H), 1.27−1.21 (m 1H), 1.14 (d, J =

6.0 Hz, 3H), 1.03−0.87 (m, 39H), 0.78 (d, J = 6.7 Hz, 3H), 0.71−0.55 (m,

24H), 0.11 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 208.6, 171.1, 144.3,

143.0, 125.0, 115.1, 81.0, 78.3, 77.7, 66.1, 65.7, 63.0, 49.8, 48.5, 46.0, 44.9,

35.4, 31.0, 28.6, 27.9, 24.6, 21.0, 19.2, 14.5, 14.2, 7.2, 7.0, 6.9, 6.8, 5.2, 4.9, 0.4;

HRMS (ES⁺) calcd for C₅₂H₁₀₈O₈Si₅Na (M + Na) 1023.6788, found

1023.6785.

Aldol Adducts 101 and 104. Method A (−100 °C Conditions). To

a stirred solution of methyl ketone 98 (574 mg, 1.17 mmol) in THF

(6 mL) at −78 °C was added LDA²(1.38 mL, 1 M in THF). After

15 min, TMEDA (400 mg, 0.310 mL, 3.44 mmol) was added. After

5 min, the reaction was cooled to −100 °C, followed by the addition of a

precooled (−100 °C) solution of aldehyde 57 (310 mg, 0.78 mmol) in

THF (6 mL) via cannula in one portion. After another 0.5 h, the reaction

was quenched with 1 M AcOH in THF (1.5 mL) at −100 °C. The

reaction mixture was then warmed up to rt, diluted with satd aq NH₄Cl

(10 mL) and extracted with ether (4 × 25 mL). The dried extract

(MgSO₄) was concentrated in vacuo and puriﬁed by chromatography

over silica gel, eluting with 50% CH₂Cl₂/hexanes −2% EtOAc/hexanes,

to give aldol adduct 104 (405 mg, 0.45 mmol, 58%) and 101 (50 mg,

0.056 mmol, 7%) as colorless oils.

Method B (−40 °C Conditions). To a stirred solution of methyl

ketone 98 (37.2 mg, 0.0758 mmol) in THF (0.4 mL) at −78 °C was

added LDA²(90 μL, 0.09 mmol, 1 M in THF). After 15 min, TMEDA

(15.5 mg, 20 μL, 0.133 mmol) was added. After 5 min, the reaction was

warmed to −40 °C, followed by the addition of a precooled (−40 °C)

solution of aldehyde 57 (20 mg, 0.0504 mmol) in THF (0.4 mL) via

cannula in one portion. After another 0.5 h, the reaction was quenched

with satd aq NH₄Cl (2 mL) and extracted with ether (4 × 5 mL). The

dried extract (MgSO₄) was concentrated in vacuo and puriﬁed

by chromatography over silica gel, eluting with 50% CH₂Cl₂/hexanes

−2% EtOAc/hexanes, to give aldol adduct 101 (16.1 mg, 0.0181 mmol,

36%) and 104 (13.4 mg, 0.0151 mmol, 30%) as colorless oils. 101:

Alcohol 105. To a stirred solution of TMS ether SI-29 (290 mg,

0.289 mmol) in THF/H₂O (6.52 mL, 8:1) at −20 °C was added HOAc

(4 × 1.45 mL) in four portions every 60 min. After 5 h, the reaction was

quenched with solid NaHCO₃, ﬁltered over Celite, and extracted with

ether (4 × 15 mL). The dried extract (MgSO₄) was concentrated in

vacuo and puriﬁed by chromatography over silica gel, eluting with

5−10% EtOAc/hexanes, to give alcohol 105 (220 mg, 0.237 mmol,

82%) as a colorless oil: [α]²³_D= −31.6 (c 1.01, CHCl₃); IR (neat) 3510,

2956, 2912, 2877, 1744, 1720, 1458, 1414, 1368, 1239, 1062, 1006, 741

[α]²³= −9.42 (c 1.21, CHCl₃); IR (neat) 3516, 2956, 2913, 2877,

D

1743, 1719, 1458, 1414, 1370, 1249, 1116, 1088, 1008, 841, 742 cm⁻¹;

Z

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cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 5.78 (s, 1H), 5.02 (s, 1H), 4.90 (s,

1H), 4.22−4.08 (m, 4H), 3.81−3.77 (m, 1H), 3.69−3.66(m, 1H), 2.94

(dd, J = 18.3, 6.1 Hz, 1H), 2.78 (dd, J = 18.3, 5.7 Hz, 1H), 2.15 (dd, J =

13.1, 5.7 Hz, 1H), 2.04 (s, 3H), 1.93−1.60 (m, 6H), 1.83 (s, 3H), 1.45−

1.34 (m, 2H), 1.44 (s, 3H), 1.30−1.20 (m, 1H), 1.17 (d, J = 6.0 Hz, 3H),

1.04−0.87 (m, 39H), 0.82 (d, J = 6.0 Hz, 3H), 0.72−0.56 (m, 24H); ¹³C

NMR (75 MHz, CDCl₃) δ 208.8, 171.2, 144.4, 142.6, 125.2, 115.1, 81.4,

78.1, 77.7, 66.2, 65.4, 63.1, 49.7, 49.0, 45.9, 44.2, 35.3, 32.5, 28.6, 28.0,

24.3, 21.0, 19.2, 15.5, 14.6, 7.2, 7.0, 6.8, 5.3, 5.2, 4.8; HRMS (ES⁺) calcd

for C₄₉H₁₀₀O₈Si₄Na (M + Na) 951.6393, found 951.6398.

16.2, 14.7 (2C), 12.4, 7.2, 7.0, 6.9, 6.8, 5.2, 5.1, 4.9; HRMS (ES⁺) calcd for

C₆₀H₁₁₉O₁₂Si₄PNa(M + Na) 1197.7414, found 1197.7422.

Macrocycle 109. To a stirred solution of alcohol 107 (125 mg, 0.106

mmol) in CH₂Cl₂(4 mL) at rt was added TPAP (45 mg,

0.127 mmol). After 0.5 h, the reaction mixture was diluted with THF

(6.5 mL)/H₂O (16 μL), and Ba(OH)₂·8H₂O (3 × 74 mg, 0.636 mmol)

was added in three portions every 30 min. After another 2 h, the reaction

mixture was puriﬁed directly by chromatography over silica gel, eluting with

5% EtOAc/hexanes, to give macrocycle 109 (54 mg, 0.053 mmol, 50% over

two steps) as colorless crystals: [α]²³_D= −27.0 (c 0.40, CHCl₃); IR (neat)

2955, 2925, 2876, 1727, 1708, 1675, 1458, 1417, 1260, 1127, 1064, 1009,

741 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.15−7.03 (m, 1H), 6.73 (t, J =

6.9 Hz, 1H), 6.19 (d, J = 16.3 Hz, 1H), 5.78 (s, 1H), 5.00 (s, 1H), 5.05−4.97

(m, 1H), 4.82 (s, 1H), 4.18−4.09 (m, 1H), 4.11 (d, J = 5.1 Hz, 1H), 3.62−

3.58 (m, 1H), 3.00−2.93 (m, 2H), 2.85−2.70 (m, 1H), 2.62−2.50 (m, 1H),

2.37−2.21 (m, 3H), 2.15−2.00 (m, 2H), 1.91−1.63 (m, 7H), 1.80 (s, 6H),

1.45−1.35 (m, 2H), 1.41 (s, 3H), 1.25 (d, J = 6.1 Hz, 3H), 1.08−0.83 (m,

39H), 0.75−0.47 (m, 27H); ¹³C NMR (100 MHz, CDCl₃) δ 206.2, 201.0,

167.6, 147.2, 144.7, 141.8, 140.6, 132.4, 129.2, 125.8, 115.4, 80.5, 79.6, 77.9,

68.3, 64.9, 49.7, 48.6, 46.7, 43.2, 41.1, 37.5, 31.0, 29.2, 28.9, 27.8, 22.6, 21.0,

18.8, 15.6, 13.3, 12.5, 7.3, 7.1, 7.0, 5.2, 4.8; HRMS (ES⁺) calcd for

C₅₆H₁₀₆O₈Si₄Na (M + Na) 1041.6863, found 1041.6812.

Phosphonate SI-30. To a stirred solution of acid 11 (450 mg, 1.47

mmol) in PhMe (3.2 mL) at rt were added sequentially Et₃N (149 mg,

0.204 mL, 1.47 mmol) and 2,4,6-trichlorobenzoyl chloride (346 mg,

0.222 mL, 1.47 mmol). After 12 h, the resulted solution was concentrated

in vacuo. DMAP (180 mg, 1.47 mmol) was added, followed by the addition

of a solution of alcohol 105 (240 m mg, 0.258 mmol) in PhMe (5.7 mL).

After another 19 h, the reaction was quenched with satd aq NH₄Cl (8 mL)

and extracted with EtOAc (4 × 50 mL). The dried extract (MgSO₄) was

concentrated in vacuo and puriﬁed by chromatography over silica gel,

eluting with 20−60% EtOAc/hexanes, to give phosponate SI-30 (235 mg,

0.193 mmol, 78%) as a colorless oil: [α]²³_D= −23.6 (c 0.83, CHCl₃); IR

(neat) 2955, 2912, 2877, 1734, 1716, 1458, 1369, 1241, 1056, 1019,

970, 741 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 6.69 (t, J = 6.3 Hz, 1H),

5.79 (s, 1H), 5.10−5.00 (m, 1H), 5.03 (s, 1H), 4.92 (s, 1H), 4.22−4.08 (m,

8H), 3.72 (dd, J = 5.1, 3.6 Hz, 1H), 3.13 (d, J = 27.8 Hz, 2H), 2.90 (dd, J =

18.0, 5.9 Hz, 1H), 2.77 (dd, J = 17.8, 6.0 Hz, 1H), 2.68 (t, J = 7.2 Hz, 2H),

2.18−2.07 (m, 3H), 2.06 (s, 3H), 1.94−1.68 (m, 9H), 1.842 (s, 3H), 1.82 (s,

3H), 1.46 (s, 3H), 1.43−1.39 (m, 2H), 1.36 (t, J = 7.0 Hz, 6H), 1.25 (d, J =6.0

Hz, 3H), 1.03−0.92 (m, 36H), 0.90 (d, J = 6.4 Hz, 3H), 0.80 (d, J = 6.7 Hz,

3H), 0.70−0.55 (m, 24H); ¹³C NMR (75 MHz, CDCl₃) δ 208.4, 201.3,

171.1, 167.6, 144.3, 142.7, 140.5, 127.9, 125.1, 115.1, 80.9, 77.8, 77.6, 68.8,

65.6, 63.0, 62.9, 62.8, 48.7, 49.0, 45.9, 43.4, 41.7, 40.6, 35.3, 31.4, 28.6, 28.0,

27.7, 22.3, 21.0, 20.7, 19.2, 16.3, 16.2, 14.7, 14.5, 12.4, 7.2, 7.0, 6.9, 6.8, 5.3, 5.2,

4.9; HRMS (ES⁺) calcd for C₆₂H₁₂₁O₁₃Si₄PNa (M + Na) 1239.7520, found

1239.7458.

TES Ether SI-31. To a stirred solution of aldol adduct 104 (440 mg,

0.496 mmol) in CH₂Cl₂(20 mL) at rt were added sequentially DMAP

(910 mg, 7.44 mmol) and TESCl (557 mg, 0.620 mL, 3.72 mmol). After

3 h, the reaction mixture was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 2% EtOAc/hexanes, to

give TES ether SI-31 (445 mg, 0.444 mmol, 90%) as a colorless oil:

[α]²³_D= −20.0 (c 0.24, CHCl₃); IR (neat) 2955, 2912, 2877, 1744,

1717, 1458, 1249, 1127, 1069, 1008, 840, 742 cm⁻¹; ¹H NMR (300

MHz, CDCl₃) δ 5.81 (s, 1H), 5.00 (s, 1H), 4.85 (s, 1H), 4.43−4.30

(m, 1H), 4.16−4.03 (m, 3H), 3.88−3.78 (m, 1H), 3.69−3.72 (m,

1H), 2.88 (dd, J = 17.4, 4.8 Hz, 1H), 2.73 (dd, J = 17.4, 7.2 Hz, 1H),

2.13 (dd, J = 13.8, 6.0 Hz, 1H), 2.04 (s, 3H), 1.82−1.94 (m, 3H), 1.79

(s, 3H), 1.64−1.75 (m, 3H), 1.46 (s, 3H), 1.39−1.51 (m, 2H), 1.20−

1.28 (m, 1H), 1.14 (d, J = 6.0 Hz, 3H), 0.84−1.03 (m, 39H), 0.77 (d,

J = 6.6 Hz, 3H), 0.56−0.71 (m, 24H), 0.11 (s, 9H); ¹³C NMR (75

MHz, CDCl₃) δ 208.4, 171.1, 144.3, 143.8, 124.3, 114.8, 81.1, 78.4,

77.3, 66.1 (2C), 62.9, 50.3, 48.7, 45.9, 45.2, 35.2, 30.7, 28.7, 26.9,

24.7, 21.0, 19.3, 14.8, 13.8, 7.2, 7.0, 6.9, 6.7, 5.4, 5.3, 5.0, 0.3;

HRMS (ES⁺) calcd for C₅₂H₁₀₈O₈Si₅Na (M + Na) 1023.6788, found

1023.6737.

Alcohol 107. To a stirred solution of ester SI-30 (230 mg,

0.189 mmol) in MeOH (10 mL) at rt was added Ba(OH)₂·8H₂O

(66.4 mg, 0.189 mmol). After 1 h, the reaction mixture was puriﬁed

directly by chromatography over silica gel, eluting with 20−60%

EtOAc/hexanes, to give alcohol 107 (204 mg, 0.168 mmol, 89%) as a

colorless oil: [α]²³_D= −27.0 (c 0.80, CHCl₃); IR (neat) 3434, 2955,

1

2877, 1716, 1458, 1376, 1242, 1019, 742 cm⁻¹; H NMR (300 MHz,

CDCl₃): δ 6.68 (t, J = 6.8 Hz, 1H), 5.78 (s, 1H), 5.11−5.00 (m, 1H), 5.00

(s, 1H), 4.86 (s, 1H), 4.19−4.05 (m, 6H), 3.73−3.66 (m, 3H), 3.07 (d, J =

27.8 Hz, 2H), 2.93 (dd, J = 18.0, 6.1 Hz, 1H), 2.78 (dd, J = 18.3, 5.7 Hz,

1H), 2.65 (t, J = 7.1 Hz, 2H), 2.22−2.11 (m, 3H), 1.92−1.59 (m, 8H), 1.81

(s, 6H), 1.43 (s, 3H), 1.42−1.39 (m, 3H), 1.33 (t, J = 7.0 Hz, 6H), 1.23 (d,

J = 6.3 Hz, 3H), 1.02−0.85 (m, 39H), 0.78 (d, J = 6.5 Hz, 3H), 0.69−0.52

(m, 24H); ¹³C NMR (75 MHz, CDCl₃) δ 209.0, 201.4, 167.6, 144.8, 142.3,

140.5, 129.0, 125.5, 114.9, 80.8, 77.8, 77.7, 68.8, 65.6, 62.6, 62.5, 61.0, 49.5,

49.0, 46.2, 43.3, 41.6, 40.6, 40.0, 31.4, 28.3, 28.1, 27.7, 22.3, 20.7, 19.3, 16.3,

Alcohol 106. To a stirred solution of TMS ether SI-31 (432 mg,

0.43 mmol) in THF/H₂O (9 mL, 8:1) at −20 °C was added HOAc

AA

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(8 mL). After 5 h, the reaction was quenched with solid NaHCO₃,

ﬁltered over Celite and extracted with ether (4 × 20 mL). The dried

extract (MgSO₄) was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 5−10−20% EtOAc/

hexanes, to give alcohol 106 (338 mg, 0.36 mmol, 85%) as a

colorless oil: [α]²³_D= −20.8 (c 1.01, CHCl₃); IR (neat) 3503, 2955,

2912, 2877, 1744, 1720, 1458, 1414, 1367, 1239, 1007, 741 cm⁻¹; ¹H

NMR (400 MHz, CDCl₃) δ 5.85 (s, 1H), 5.02 (s, 1H), 4.86 (s, 1H),

4.50−4.40 (m, 1H), 4.18−4.03 (m, 3H), 3.85−3.77 (m, 1H), 3.67 (t,

J = 5.0 Hz, 1H), 2.74−2.86 (m, 2H), 2.19 (br, OH), 2.14 (dd, J = 13.6,

6.3 Hz, 1H), 2.06 (s, 3H), 1.89−1.96 (m, 2H), 1.80 (s, 3H), 1.66−

1.85 (m, 5H), 1.45 (s, 3H), 1.39−1.42 (m, 1H), 1.19 (d, J = 6.0 Hz,

3H), 1.10−1.22 (m, 1H), 0.95−1.05 (m, 36H), 0.90 (d, J = 6.4 Hz,

3H), 0.85 (d, J = 6.4 Hz, 3H), 0.59−0.72 (m, 24H); ¹³C NMR

(100 MHz, CDCl₃) δ 208.4, 171.2, 144.3, 143.5, 124.4, 115.0, 82.1,

78.5, 77.3, 66.0, 65.9, 63.0, 50.0, 48.0, 45.9, 44.4, 35.2, 32.3, 28.7,

27.3, 24.2, 21.0, 19.3, 15.4, 15.0, 7.3, 7.1, 7.0, 6.9, 6.8, 5.3, 5.2, 4.9;

HRMS (ES⁺) calcd for C₄₉H₁₀₀O₈Si₄Na (M + Na) 951.6393, found

951.6418.

2955, 2877, 1716, 1458, 1242, 1019, 969, 742 cm⁻¹; ¹H NMR (300

MHz, CDCl₃): δ 6.69 (t, J = 6.2 Hz, 1H), 5.82 (s, 1H), 5.10−5.03 (m,

1H), 5.00 (s, 1H), 4.83 (s, 1H), 4.42−4.31 (m, 1H), 4.20−4.08 (m,

5H), 3.63−3.74 (m, 3H), 3.12 (d, J = 22.8 Hz, 2H), 2.78−2.72 (m,

2H), 2.66 (t, J = 7.1 Hz, 2H), 2.04−2.19 (m, 3H), 1.89−1.61 (m,

10H), 1.81 (s, 3H), 1.78 (s, 3H), 1.44 (s, 3H), 1.43−1.38 (m, 1H),

1.35 (t, J = 7.1 Hz, 6H), 1.24 (d, J = 5.9 Hz, 3H), 1.03−0.92 (m, 36H),

0.87 (d, J = 6.4 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H), 0.55−0.71 (m,

24H); ¹³C NMR (100 MHz, CDCl₃) δ 208.5, 201.5, 167.7, 144.6,

143.5, 140.6, 129.0, 124.7, 114.7, 81.2, 78.0, 68.8, 66.1, 62.6, 62.5,

61.1, 50.3, 49.1, 46.1, 43.5, 43.4, 41.8, 40.9, 39.8, 31.1, 28.5, 27.8,

27.1, 22.3, 20.8, 19.5, 16.4, 16.3, 14.9, 14.2, 12.4, 7.3, 7.1, 7.0, 6.9, 6.8,

5.3, 5.2, 5.0; HRMS (ES⁺) calcd for C₆₀H₁₁₉O₁₂Si₄PNa (M + Na)

1197.7414, found 1197.7423.

Macrocycle 110. To a stirred solution of alcohol 108 (170 mg,

0.144 mmol) in CH₂Cl₂(4 mL) at rt was added TPAP (61 mg,

0.173 mmol). After 0.5 h, the reaction mixture was diluted with CH₂Cl₂

(3 mL)/CH₃CN (7 mL) and Hunig’s base (297 mg, 0.4 mL, 2.29 mmol)

was added, followed by the addition of LiCl (20 mg, 0.476 mmol). After

24 h, the reaction mixture was puriﬁed directly by chromatography over

silica gel, eluting with 5% EtOAc/hexanes, to give macrocycle 110

Phosphonate SI-32. To a stirred solution of acid 11 (837 mg, 2.73

mmol) in PhMe (6 mL) at rt were added sequentially Et₃N (276 mg,

0.379 mL, 2.73 mmol) and 2,4,6-trichlorobenzoyl chloride (641 mg,

0.411 mL, 2.73 mmol). After 12 h, the resulted solution was

concentrated in vacuo. DMAP (333 mg, 2.73 mmol) was added,

followed by the addition of a solution of alcohol 106 (445 mg, 0.479

mmol) in PhMe (10.5 mL). After another 19 h, the reaction was

quenched with satd aq NH₄Cl (15 mL) and extracted with EtOAc (4 ×

50 mL). The dried extract (MgSO₄) was concentrated in vacuo and

puriﬁed by chromatography over silica gel, eluting with 20−60%

EtOAc/hexanes, to give phosphonate SI-32 (450 mg, 0.100 mmol, 77%)

as a colorless oil: [α]²³_D= −20.3 (c 1.23, CHCl₃); IR (neat) 2955, 2913,

(75 mg, 0.073 mmol, 51% over two steps) as a colorless oil: [α]²³

=

D

−10.0 (c 0.62, CHCl₃); IR (neat) 2955, 2913, 2876, 1708, 1674, 1457,

1

1417, 1375, 1240, 1124, 1072, 1008, 742 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 6.88 (dt, J = 16.2, 7.4 Hz, 1H), 6.72 (t, J = 8.0 Hz, 1H), 6.10

(d, J = 16.0 Hz, 1H), 5.82 (s, 1H), 5.08−4.99 (m, 1H), 5.02 (s, 1H), 4.87

(s, 1H), 4.30−4.22 (m, 1H), 4.01 (d, J = 6.4 Hz, 1H), 3.58 (dd, J = 6.4,

2.7 Hz, 1H), 2.86 (dd, J = 17.4, 8.6 Hz, 1H), 2.77 (dd, J = 15.4, 6.0 Hz,

1H), 2.62−2.54 (m, 2H), 2.36−2.19 (m, 4H), 2.14 (dd, J = 17.4, 8.6

Hz, 1H), 2.05−1.76 (m, 7H), 1.80 (s, 3H), 1.79 (s, 3H), 1.70−1.60 (m,

1H), 1.57−1.51 (m, 1H), 1.41 (s, 3H), 1.25 (d, J = 6.2 Hz, 3H), 1.05−

0.93 (m, 36H), 0.84 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H), 0.73−

0.58 (m, 24H); ¹³C NMR (100 MHz, CDCl₃) δ 208.1. 201.0, 167.6,

147.3, 147.1, 144.0, 142.8, 140.8, 132.4, 129.3, 124.7, 115.1, 80.6, 77.4

(2C), 68.5, 65.1, 50.6, 49.0, 46.1, 41.7, 40.2, 37.2, 31.3, 30.8, 27.8, 27.4,

23.1, 21.0, 19.7, 15.3, 12.8, 12.5, 7.3, 7.1, 7.0, 6.9, 5.3, 5.2, 4.9; HRMS

(ES⁺) calcd for C₅₆H₁₀₆O₈Si₄Na (M + Na) 1041.6863, found

1041.6824.

1

2877, 1740, 1716, 1458, 1368, 1243, 1056, 1019, 968, 742 cm⁻¹; H

NMR (300 MHz, CDCl₃) δ 6.69 (t, J = 6.4 Hz, 1H), 5.82 (s, 1H), 5.10−

5.02 (m, 1H), 5.01 (s, 1H), 4.84 (s, 1H), 4.42−4.32 (m, 1H), 4.21−4.02

(m, 7H), 3.76−3.68 (m, 1H), 3.12 (d, J = 22.8 Hz, 2H), 2.85 (dd, J =

17.4, 4.1 Hz, 1H), 2.65−2.76 (m, 3H), 2.12−2.22 (m, 2H), 2.10−2.04

(m, 1H), 2.05 (s, 3H), 1.58−1.93 (m, 10H), 1.82 (s, 3H), 1.79 (s, 3H),

1.45 (s, 3H), 1.43−1.39 (m, 1H), 1.35 (t, J = 7.1 Hz, 6H), 1.24 (d, J = 5.9

Hz, 3H), 0.87−1.03 (m, 39H), 0.79 (d, J = 6.6 Hz, 3H), 0.55−0.68 (m,

24H); ¹³C NMR (75 MHz, CDCl₃) δ 208.3, 201.4, 171.1, 167.6, 144.3,

143.7, 140.5, 129.0, 124.4, 114.9, 81.1, 77.9, 77.34, 68.8, 66.2, 62.9, 62.6,

62.5, 50.3, 49.0, 45.9, 43.3, 41.6, 40.8, 35.2, 31.1, 28.7, 27.7, 26.9, 22.3,

21.0, 20.7, 19.3, 16.3, 16.2, 14.8, 14.3, 12.4, 7.2, 7.1, 7.0, 6.9, 6.7, 5.3, 5.2,

5.0; HRMS (ES⁺) calcd for C₆₂H₁₂₁O₁₃Si₄PNa (M + Na) 1239.7520,

found 1239.7563.

Allylic Alcohol 111. To a stirred solution of macrocycle 110

(107 mg, 0.105 mmol) in CH₂Cl₂(5.4 mL) at −20 °C were added

sequentially (S)-CBS (0.42 mL, 0.42 mmol, 1 M in PhMe) and

BH₃·DMS (0.84 mL, 0.84 mmol, 1 M in THF). After 45 min, the

reaction was quenched with MeOH (0.3 mL), diluted with aq

NaHCO₃(5 mL), and extracted with Et₂O (3 × 8 mL). The dried

extract (MgSO₄) was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 3−6% EtOAc/hexanes,

to give allylic alcohol 111 (72 mg, 0.0704 mmol, 67%) as a colorless oil:

Alcohol 108. To a stirred solution of ester SI-32 (170 mg,

0.140 mmol) in MeOH (0.5 mL) at rt was added a saturated solution of

Ba(OH)₂·8H₂O in MeOH (6.0 mL). After 20 min, the reaction mixture

was puriﬁed directly by chromatography over silica gel, eluting with

20−60% EtOAc/hexanes, to give alcohol 108 (150 mg, 0.127 mmol,

91%) as a colorless oil: [α]²³_D= −20.3 (c 0.60, CHCl₃); IR (neat) 3440,

[α]²³= −16.3 (c 0.30, CHCl₃); IR (neat) 3431, 2954, 2913, 2876,

D

1708, 1674, 1458, 1414, 1376, 1241, 1128, 1073, 1009, 742 cm⁻¹; ¹H

NMR (400 MHz, CDCl₃) δ 6.80 (t, J = 8.0 Hz, 1H), 5.89 (s, 1H),

5.63−5.52 (m, 1H), 5.45 (dd, J = 15.4, 7.5 Hz, 1H), 5.10−5.00

AB

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(m, 1H), 4.98 (s, 1H), 4.82 (s, 1H), 4.32−4.20 (m, 1H), 4.19−4.09

(m, 1H), 4.04 (d, J = 6.2 Hz, 1H), 3.57 (dd, J = 6.2, 2.5 Hz, 1H),

2.87 (dd, J = 17.0, 9.0 Hz, 1H), 2.49 (d, J = 16.8 Hz, 1H), 2.28−2.20

(m, 2H), 2.13−1.98 (m, 3H), 1.90−1.61 (m, 9H), 1.86 (s, 3H), 1.75 (s,

3H), 1.55−1.46 (m, 2H), 1.39 (s, 3H), 1.26 (d, J = 6.0 Hz, 3H), 1.06−0.94

(m, 36H), 0.82 (d, J = 6.4 Hz, 3H), 0.73−0.60 (m, 27H); ¹³C NMR

(100 MHz, CDCl₃) δ 208.5, 167.8, 144.6, 142.0, 141.3, 134.6, 130.8, 128.2,

125.4, 114.4, 80.6, 78.0, 72.9, 68.4, 65.2, 50.3, 49.2, 45.4, 41.8, 39.7, 36.8,

31.3, 30.4, 28.8, 28.2, 24.0, 20.9, 19.6, 15.4, 12.5, 12.4, 7.3, 7.1, 7.0, 5.3, 5.2,

4.9; HRMS (ES⁺) calcd for C₅₆H₁₀₈O₈Si₄Na (M + Na) 1043.7019, found

1043.7052.

Selenide 115. To a stirred solution of epoxide 113 (42 mg, 0.0405

mmol) in THF (2 mL) at rt were added sequentially o-NO₂C₆H₄SeCN

(184 mg, 0.809 mmol) and PBu₃(164 mg, 202 μL, 0.809 mmol). After

5 h, the reaction mixture was concentrated in vacuo puriﬁed by chromato-

graphy over silica gel, eluting with hexanes then with 4% EtOAc/hexanes,

to give crude selenide 115 (30 mg) as a yellow oils which was used directly

in next step without further puriﬁcation.

Polyol SI-33. To a stirred solution of selenide 115 (30 mg) in THF/

DMF/H₂O (10:1:0.02, 1.8 mL/180 μL/3.6 μL) at 0 °C was added

TAS-F (33.7 mg, 0.123 mmol). The reaction mixture was then warmed

to rt. After 2 h, the reaction mixture was concentrated in vacuo and

puriﬁed by chromatography over silica gel, eluting with 10−65%

EtOAc/hexanes, to give polyol SI-33 (15 mg, 0.0196 mmol, 48% over

two steps) as a yellow solid: [α]²³_D= −20.1 (c 0.12, CHCl₃); IR (neat)

Epoxide 113 and 112. To a stirred solution of allylic alcohol 111 (70

mg, 0.0685 mmol) in CH₂Cl₂(6 mL) at −20 °C were added sequentially 4 Å

MS (50 mg), TBHP (37 μL, 0.206 mmol, 5.5 M in decane), and Ti(O-i-Pr)₄

(23.3 mg, 24 μL, 0.082 mmol). After 5 h, the reaction was quenched with aq

NaHCO₃(3 mL) and extracted with Et₂O (3 × 7 mL). The dried extract

(MgSO₄) was concentrated in vacuo and puriﬁed by chromatography over silica

gel, eluting with 6−10% EtOAc/hexanes, to give epoxide 113 (35 mg, 0.0342

mmol, 50%) and epoxide 112 (17 mg, 0.0166 mmol, 24%) as colorless oils.

113: [α]²³_D= −29.0 (c 0.42, CHCl₃); IR (neat) 3431, 2954, 2923, 2876, 1708,

1647, 1458, 1414, 1377, 1242, 1128, 1073, 1009, 742 cm⁻¹; ¹H NMR (400

MHz, CDCl₃)δ6.78 (t, J = 8.0 Hz, 1H), 5.88 (s, 1H), 5.05−4.98(m, 1H), 5.01

(s,1H),4.86(s, 1H), 4.30−4.20(m, 1H), 4.05(d,J = 6.1 Hz, 1H), 3.59 (dd, J =

6.1, 2.0 Hz, 1H), 3.52−3.43(m,1H),3.22−3.15 (m, 1H), 2.91 (dd, J = 16.3, 9.1

Hz, 1H), 2.70 (dd, J = 6.0, 2.0 Hz, 1H), 2.44−2.25 (m, 3H), 2.18 (dd, J = 13.0,

5.6 Hz, 1H), 2.10−1.63 (m, 12H), 1.87 (s, 3H), 1.78 (s, 3H), 1.41 (s, 3H), 1.26

(d, J = 6.0 Hz, 3H), 1.15−1.09 (m, 1H), 1.07−0.89 (m, 36H), 0.80 (d, J = 6.4

Hz, 3H), 0.76−0.59 (m, 27H); ¹³C NMR (100 MHz, CDCl₃) δ 208.4, 167.7,

144.0, 142.1, 141.4, 128.6, 125.0, 114.9, 80.8, 78.2, 77.5, 71.8, 68.3,

65.6, 62.8, 56.4, 50.6, 49.1, 46.6, 42.1, 38.9, 33.1, 30.1, 29.4, 28.8, 28.3,

23.7, 21.0, 19.8, 15.5, 12.5, 12.4, 7.3, 7.1, 7.0, 5.3, 5.2, 5.0; HRMS (ES⁺)

calcd for C₅₆H₁₀₈O₉Si₄Na (M + Na) 1059.6968, found 1059.7009. 112:

[α]_D= −26.2 (c 0.60, CHCl₃); IR (neat) 3482, 2954, 2923, 2876, 1708,

1

3447, 2925, 2854, 1701, 1520, 1456, 1334, 1273, 759, 732 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 8.28 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 7.8

Hz, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 6.81 (t, J = 6.4

Hz, 1H), 6.05 (s, 1H), 5.10−5.00 (m, 1H), 5.02 (s, 1H), 4.80 (s, 1H),

4.38 (d, J = 3.6 Hz, 1H), 4.18 (s, 1H), 4.17−4.11 (m, 1H), 4.07 (t, J =

9.6 Hz, 1H), 3.58 (t, J = 8.6 Hz, 1H), 3.18−3.10 (m, 1H), 2.97 (d, J =

8.1 Hz, 1H), 2.79 (dd, J = 12.8, 10.1 Hz, 1H), 2.37−2.28 (m, 1H),

2.40−2.30 (m, 1H), 2.22−2.04 (m, 3H), 1.94−1.76 (m, 7H), 1.83 (s,

3H), 1.79 (s, 3H), 1.72−1.62 (m, 3H), 1.38 (s, 3H), 1.31 (d, J = 6.1

Hz, 3H), 1.25−1.19 (m, 2H), 1.07 (d, J = 6.4 Hz, 3H), 0.83 (d, J = 6.2

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 211.1, 167.6, 149.6, 144.4,

141.0 (2C), 133.1, 132.5, 128.9, 128.3, 127.0, 126.0, 125.1, 115.0,

78.3, 77.5, 75.3, 68.7, 68.3, 62.3, 59.3, 46.7, 45.7, 45.5, 43.8, 40.4,

40.0, 32.8, 31.6, 29.1, 29.0, 28.1, 26.1, 21.2, 17.7, 16.2, 15.3, 12.5;

HRMS (ES⁺) calcd for C₃₈H₅₅NO₁₀NaSe (M + Na) 788.2889, found

788.2859.

1

1458, 1414, 1377, 1240, 1128, 1008, 742 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 6.79 (t, J = 7.7 Hz, 1H), 5.87 (s, 1H), 5.05−4.98 (m, 1H), 4.99 (s,

1H), 4.84 (s, 1H), 4.30−4.20 (m, 1H), 4.09 (d, J = 5.9 Hz, 1H), 3.75−3.69

(m, 1H), 3.57 (dd, J = 5.6, 3.2 Hz, 1H), 2.91−2.78 (m, 3H), 2.68−2.60 (m,

2H), 2.38−2.20 (m, 3H), 2.07 (dd, J = 12.9, 6.2 Hz, 1H), 1.93−1.62 (m,

10H), 1.85 (s, 3H), 1.76 (s, 3H), 1.50−1.44 (m, 2H), 1.40 (s, 3H), 1.25 (d, J

= 6.0 Hz, 3H), 1.05−0.93 (m, 39H), 0.74−0.59 (m, 27H); ¹³C NMR (100

MHz, CDCl₃) δ 208.6, 167.8, 144.1, 142.5, 141.5, 128.4, 124.9, 114.9, 81.0,

78.2, 77.4, 69.0, 68.4, 65.5, 60.7, 54.9, 50.3, 49.2, 46.3, 41.7, 38.4, 33.3, 30.7,

30.3, 29.0, 27.9, 23.7, 21.0, 20.0, 15.3, 13.2, 12.4, 7.3, 7.1, 7.0, 6.9, 5.3, 5.2, 4.9;

HRMS (ES⁺) calcd for C₅₆H₁₀₈O₉Si₄Na (M + Na) 1059.6968, found

1059.7009.

Proposed Structure of Amphidinolide B₂(3). To a stirred

solution of selenide SI-33 (6.0 mg, 0.00784 mmol) in CH₂Cl₂(1.2 mL) at rt

were added sequentially NaHCO₃(60 mg, 0.714 mmol) and TMSOOTMS

(41.7 mg, 50 μL, 0.233 mmol). After 1.5 h, the yellow color vanished and the

reaction mixture was puriﬁed by preparative TLC, eluting with 60% EtOAc/

hexanes, to give allylic epoxide 3 (3.0 mg, 0.00533 mmol, 68%): [α]²³

=

D

−52.3 (c 0.21, CHCl₃); IR (neat) 3446, 2923, 2853, 1701, 1457, 1273, 1120

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.74 (t, J = 6.4 Hz, 1H), 6.06 (s, 1H),

5.92 (ddd, J = 15.0, 8.9, 4.4 Hz, 1H), 5.20 (dd, J = 15.5, 8.8 Hz, 1H), 5.11−

5.07 (m, 1H), 5.07 (s, 1H), 4.86 (s, 1H), 4.28 (d, J = 5.4, 1H), 4.14 (s, OH),

4.14−4.09 (m, 1H), 3.73 (d, J = 5.6 Hz, OH), 3.69 (t, J = 9.5 Hz, 1H), 3.50

(d, J = 6.8 Hz, 1H), 3.23 (dd, J = 8.7, 2.2 Hz, 1H), 3.08−3.03 (m, 2H), 2.95

AC

dx.doi.org/10.1021/jo3026077 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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(d, J = 9.2 Hz, OH), 2.53−2.45 (m, 1H), 2.45−2.36 (m, 1H), 2.28 (dd, J =

13.2, 1.8 Hz, 1H), 2.17−2.12 (m, 3H), 1.97−1.93 (m, 4H), 1.85 (s, 3H),

1.82−1.79 (m, 1H), 1.80 (s, 3H), 1.78−1.75 (m, 1H), 1.64−1.60 (m, 1H),

1.34 (s, 3H), 1.31 (d, J = 6.1 Hz, 3H), 1.17−1.12 (m, 1H), 1.03 (d, J =6.7Hz,

3H), 0.98 (d, J = 5.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 212.5, 167.7,

144.7, 141.6, 139.5, 136.3, 128.4, 128.3, 124.9, 114.6, 78.1, 75.6, 69.28, 68.23,

61.45, 59.5, 47.1, 46.4, 44.1, 40.0, 39.4, 33.3, 31.0, 29.3, 28.3, 26.7, 21.2, 17.5,

15.9, 15.2, 12.6; HRMS (ES⁺) calcd for C₃₂H₅₀O₈Na (M + Na) 585.3403,

found 585.3390.

Allylic Epoxide 114. To a stirred solution of selenide SI-35

(2.5 mg, 0.00327 mmol) in CH₂Cl₂(0.5 mL) at rt were added

sequentially NaHCO₃(20 mg, 0.238 mmol) and TMSO−OTMS

(19.1 mg, 23 μL, 0.107 mmol). After 1.5 h, the yellow color vanished

and the reaction mixture was puriﬁed by preparative TLC, eluting

with 60% EtOAc/hexanes, to give allylic epoxide 114 (1.2 mg,

0.00213 mmol, 65%): [α]_D= −27.5 (c 0.12, CHCl₃); IR (neat)

1

3443, 2924, 2852, 1703, 1457, 1379, 1272, 1118 cm⁻¹; H NMR

(300 MHz, CDCl₃) δ 6.71−6.63 (m, 1H), 6.08 (s, 1H), 5.88−5.78

(m, 1H), 5.26 (dd, J = 15.1, 8.4 Hz, 1H), 5.12−5.05 (m, 1H), 5.05

(s, 1H), 4.84 (s, 1H), 4.29 (dd, J = 5.7, 1.5 Hz, 1H), 4.30−4.20 (m,

1H), 3.71 (t, J = 7.9 Hz, 1H), 3.66 (d, J = 5.7 Hz, 1H), 3.19 (d, J = 9.6

Hz, 1H), 3.12 (dd, J = 8.6, 2.2 Hz, 1H), 3.01−2.87 (m, 2H), 2.46

(dd, J = 14.4, 2.1 Hz, 1H), 2.36−2.20 (m, 5H), 2.00−1.74 (m, 6H),

1.83 (s, 3H), 1.77 (s, 3H), 1.60−1.55 (m, 1H), 1.35 (s, 3H), 1.33−

1.28 (m, 1H), 1.30 (d, J = 6.1 Hz, 3H), 1.18−1.11 (m, 1H), 1.03 (d,

J = 6.6 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 212.9, 167.5, 144.9, 141.6, 140.3, 136.4, 128.7, 128.6,

125.7, 115.0, 78.2, 76.6, 75.9, 68.5, 68.2, 60.2, 60.0, 45.8, 45.1, 43.8,

39.4, 39.3, 33.6, 31.0, 30.3, 28.5, 27.0, 21.2, 20.0, 15.8, 15.2, 12.7;

HRMS (ES⁺) calcd for C₃₂H₅₀O₈Na (M + Na) 585.3403, found

585.3394.

Selenide SI-34. To a stirred solution of epoxide 112 (12 mg,

0.0116 mmol) in THF (0.7 mL) at rt were added sequentially

o-NO₂C₆H₄SeCN (53 mg, 0.232 mmol) and PBu₃(47 mg, 58 μL, 0.232

mmol). After 0.5 h, the reaction mixture was concentrated in vacuo

puriﬁed by chromatography over silica gel, eluting with Hexanes then

with 4% EtOAc/hexanes, to give crude selenide SI-34 (10.6 mg) as a

yellow oil which was used directly in next step without further

puriﬁcation.

Polyol SI-35. To a stirred solution of selenide SI-34 (10.6 mg) in

THF/DMF/H₂O (10:1:0.02, 1.0 mL/100 μL/2.0 μL) at 0 °C

was added TAS-F (12 mg, 0.0434 mmol). The reaction mixture

was then warmed to rt. After 2 h, the reaction mixture was

concentrated in vacuo and puriﬁed by chromatography over silica

gel, eluting with 10−65% EtOAc/hexanes, to give polyol SI-35

(6.2 mg, 0.00811 mmol, 70% over two steps) as a yellow oil: [α]_D=

−47.0 (c 0.30, CHCl₃); IR (neat) 3446, 2925, 2854, 1701, 1515,

1456, 1332, 1271, 757, 731 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.16

(d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H),

7.42 (t, J = 7.8 Hz, 1H), 6.85 (t, J = 6.3 Hz, 1H), 6.02 (s, 1H), 5.11−

5.05 (m, 1H), 5.04 (s, 1H), 4.81 (s, 1H), 4.38 (d, J = 3.6 Hz, 1H),

4.32−4.25 (m, 1H), 4.17−4.12 (m, 1H), 3.89 (d, J = 4.6 Hz, 1H),

3.72−3.65 (m, 1H), 3.62−3.55 (m, 1H), 3.10−3.05 (m, 2H), 2.84

(dd, J = 14.8, 9.2 Hz, 1H), 2.52 (dd, J = 14.8, 2.5 Hz, 1H), 2.38 (d, J =

9.5 Hz, 1H), 2.40−2.20 (m, 3h), 1.97−1.74 (m, 8H), 1.83 (s, 3H),

1.76 (s, 3H), 1.70−1.60 (m, 3H), 1.36 (s, 3H), 1.33 (d, J = 6.1 Hz,

3H), 1.06 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.2 Hz, 3H); ¹³C NMR

(100 MHz, CDCl₃) δ 212.0, 167.7, 147.7, 144.6, 141.3, 140.9,

133.7, 132.3, 130.1, 128.6, 126.5, 126.1, 125.6, 115.1, 78.0, 77.0,

75.5, 69.1, 67.7, 60.6, 58.4, 45.7, 45.6, 43.7, 43.1, 40.4, 39.2, 33.8,

30.3, 29.5, 28.9, 28.0, 27.0, 21.2, 19.7, 16.3, 15.2, 12.5; HRMS

(ES⁺) calcd for C₃₈H₅₅NO₁₀NaSe (M + Na) 788.2889, found

788.2897.

Allylic Alcohols 118 and 119. To a stirred solution of macrocycle

109 (50 mg, 0.049 mmol) in CH₂Cl₂(2.3 mL) at −30 °C were added

sequentially (S)-CBS (0.196 mL, 0.196 mmol, 1 M in PhMe) and

BH₃·DMS (0.3934 mL, 0.393 mmol, 1 M in THF). After 45 min, the

reaction was quenched with MeOH (0.3 mL), diluted with aq

NaHCO₃(3 mL), and extracted with Et₂O (4 × 6 mL). The dried

extract (MgSO₄) was concentrated in vacuo and puriﬁed by

chromatography over silica gel, eluting with 3−6% EtOAc/hexanes,

to give allylic alcohol 118 (29 mg, 0.028 mmol, 58%) and SI-36 (8

mg, 0.0078 mmol, 16%) as colorless oils. 118: [α]²³_D= −23.6 (c 0.25,

CHCl₃); IR (neat) 3503, 2954, 2911, 2876, 1707, 1458, 1376, 1240,

1128, 1007, 742 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.81 (t, J = 6.9

Hz, 1H), 5.76 (s, 1H), 5.70−5.62 (m, 1H), 5.53 (dd, J = 13.2, 6.3 Hz,

1H), 5.00−4.95 (m, 1H), 4.98 (s, 1H), 4.84 (s, 1H), 4.15−4.04 (m,

3H), 3.58 (dd, J = 5.7, 2.4 Hz, 1H), 2.93 (dd, J = 18.4, 6.2 Hz, 1H),

2.78 (dd, J = 18.4, 6.0 Hz, 1H), 2.28−2.22 (m, 2H), 2.18−2.10 (m,

2H), 2.08−1.99 (m, 1H), 1.89−1.57 (m, 9H), 1.84 (s, 3H), 1.81 (s,

3H), 1.48−1.40 (m, 2H), 1.45 (s, 3H), 1.26 (d, J = 6.1 Hz, 3H), 1.07−

0.91 (m, 36H), 0.88 (d, J = 6.6 Hz, 3H), 0.74−0.53 (m, 27H); ¹³C

NMR (100 MHz, CDCl₃) δ 207.8, 167.8, 145.5, 142.5 (2C), 134.9,

129.7, 127.9, 125.7, 114.9, 80.6, 79.2, 77.9, 71.9, 68.2, 65.3, 49.6, 49.2,

45.6, 42.2, 39.4, 37.0, 31.8, 29.8, 29.0, 28.1, 23.6, 21.0, 19.9, 14.7,

12.7, 12.4, 7.2, 7.1, 7.0, 6.9, 6.8, 5.3, 5.2, 4.7; HRMS (ES⁺) calcd for

C₅₆H₁₀₈O₈Si₄Na (M + Na) 1043.7019, found 1043.7072. SI-36:

[α]_D= −29.1 (c 0.80, CHCl₃); IR (neat) 3481, 2954, 2876, 1707,

1

1458, 1241, 1130, 1008, 742 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

6.74 (t, J = 7.4 Hz, 1H), 5.77 (s, 1H), 5.75−5.70 (m, 1H), 5.55 (dd,

J = 15.5, 7.0 Hz, 1H), 5.00−4.96 (m, 1H), 4.99 (s, 1H), 4.83 (s, 1H),

4.22−4.15 (m, 1H), 4.11−4.06 (m, 1H), 4.07 (d, J = 5.8 Hz, 1H),

AD

dx.doi.org/10.1021/jo3026077 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Amphidinolide B: Total synthesis, structural investigation, and biological evaluation

DOI: 10.1021/jo3026077

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