Total synthesis of (+)-irciniastatin A (a.k.a. psymberin) and (-)-irciniastatin B

Article

pubs.acs.org/joc

Total Synthesis of (+)-Irciniastatin A (a.k.a. Psymberin) and

(−)-Irciniastatin B

Chihui An, Jon A. Jurica, Shawn P. Walsh, Adam T. Hoye, and Amos B. Smith, III*

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

Pennsylvania, Philadelphia, Pennsylvania 19104, United States

S

* Supporting Information

ABSTRACT: A uniﬁed synthetic strategy to access (+)-irci-

niastatin A (a.k.a. psymberin) and (−)-irciniastatin B, two

cytotoxic secondary metabolites, has been achieved. Highlights

of the convergent strategy comprise a boron-mediated aldol

union to set the C(15)−C(17) syn−syn triad, reagent control

to set the four stereocenters of the tetrahydropyran core, and a

late-stage Curtius rearrangement to install the acid-sensitive stereogenic N,O-aminal. Having achieved the total synthesis of

(+)-irciniastatin A, we devised an improved synthetic route to the tetrahydropyran core (13 steps) compared to the ﬁrst-

generation synthesis (22 steps). Construction of the structurally similar (−)-irciniastatin B was then achieved via modiﬁcation of

a late-stage (−)-irciniastatin A intermediate to implement a chemoselective deprotection/oxidation sequence to access the

requisite oxidation state at C(11) of the tetrahydropyran core. Of particular signiﬁcance, the uniﬁed strategy will permit late-stage

diversiﬁcation for analogue development, designed to explore the biological role of substitution at the C(11) position of these

highly potent tumor cell growth inhibitory molecules.

This eﬀort not only yielded the absolute conﬁguration of

(+)-psymberin, but conﬁrmed that both (+)-irciniastatin A (1)

and (+)-psymberin possessed identical chemical structures.³

More recently, De Brabander reported a full account on their

ﬁrst- and second-generation synthesis of (+)-irciniastatin A (1)

(a.k.a. psymberin), in conjunction with the synthesis of a series of

novel analogues.⁴

INTRODUCTION

■

In 2004 two new potent cytotoxins, (+)-irciniastatin A (1) and

(−)-irciniastatin B (2), isolated from the Indo-Paciﬁc marine

sponge Ircinia ramose, were discovered by Pettit and co-workers

(Figure 1).¹In the same year, a closely related metabolite,

The discovery that (+)-irciniastatin A (1) (a.k.a. psymberin)

and (−)-irciniastatin B (2) display impressive therapeutic

properties, including tumor cell growth inhibition at the

nanomolar level (0.7 to 0.8 nM),¹in conjunction with the

observation by Crews et al. that (+)-irciniastatin A (1) displayed

high diﬀerential cytotoxicity (>10 000-fold) in the NCI 60

human tumor cell panel, raised the intriguing possibility that the

observed cytotoxicity might arise via a novel mode of action.²

Interestingly, even though the chemical structures of (+)-irci-

niastatin A (1) and (−)-irciniastatin B (2) diﬀer only in the

oxidation level at C(11), the ketone congener (2) was reported

to be nearly 10 times more active than the alcohol (1) against

human pancreas (BXPC-3), breast (MCF-7), and central

nervous system (SF268) cancer cell lines.¹Subsequently, a

group at Schering-Plough⁵reported that (+)-C(11)-deoxy-

analogue possesses 3−10 times the cytotoxic activity compared

to (1). Taken together, these results suggest that the C(11)

hydroxyl group is not critical for potent cytotoxic activity.

In 2010 Usui and co-workers reported that the tumor growth

inhibition activity of (+)-irciniastatin A (1) arises from activation

of stress-activated protein kinases, such as JNK and p38, that in

Figure 1. Irciniastatin family.

(+)-psymberin, was isolated independently by Crews and co-

workers from marine sponge Psamminocinia.²Analysis of these

reports suggests that irciniastatin A (1), irciniastatin B (2), and

psymberin (1) possessed the same architectural features,

including a highly substituted 2,6-trans-tetrahydropyran core, a

dihydroisocoumarin, and an N,O-aminal. Crews postulated that

both irciniastatin A (1) and psymberin might be identical,²but

unfortunately the NMR spectra of the two congeners were taken

in diﬀerent solvents, and thus the exact stereochemical

relationship at C(4) and C(8) could not be established. In

2005, De Brabander and colleagues resolved the structural

ambiguity with the ﬁrst total synthesis of psymberin by

construction of all four C(4)−C(8) diastereomers of psymberin.

Received: February 4, 2013

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turn leads to apoptosis.⁶Subsequent to this report, De

Brabander, in collaboration with Roth, disclosed a forward

genetic screen of (+)-irciniastatin A (1) employing Caeno-

rhabditis elegans that demonstrated 1 binds to the ribosome to

induce cell death.⁷Also of interest, totally synthetic (+)-ircinias-

tatin A (1), from the De Brabander group, did not reveal the high

diﬀerential cytotoxicity⁷previously reported for natural

(+)-irciniastatin A (1).²

Scheme 1. Retrosynthetic Analysis

Given the impressive biological activity, in conjunction with

limited natural abundance of the irciniastatins, seven total

syntheses^3,8−13of (+)-irciniastatin A (1), including a report from

our laboratory,⁹have been disclosed since 2004. After

DeBrabander’s seminal total synthesis,³Floreancig’s clever

strategy to installing the N,O-aminal to construct (1) proved

to be the shortest longest linear sequence to date (14 steps).¹³

Somewhat more surprising, the ﬁrst total synthesis of the

substantially more active congener, (−)-irciniastatin B (2), was

only recently achieved in our laboratory.¹⁴Although several SAR

studies have shed some light on the mode of action of

(+)-irciniastatin A (1), the biological properties associated with

the structural diﬀerences of the alcohol (1) and the ketone (2)

remain unknown. In particular, we were interested in what role

the C(11) substituents in the irciniastatins would play in an SAR

study. Toward this end, we report here a full account of the

synthesis of both (+)-irciniastatin A (1) and (−)-irciniastatin B

(2), including our ﬁrst-generation synthesis of (+)-irciniastatin A

(1), a revised second-generation synthesis of the 2,6-trans-

tetrahydropyran core of (+)-irciniastatin A (1), and the

subsequent development of a uniﬁed strategy, utilizing a late-

stage selective deprotection/oxidation sequence, which not only

led to the ﬁrst synthesis of (−)-irciniastatin B (2), but also the

construction of both C(11) alcohol epimers.

Scheme 2. Synthesis of Acid Side Chain (−)-3

RESULTS AND DISCUSSION

■

First-Generation Synthesis of (+)-Irciniastatin A (1). Our

strategy to construct (+)-irciniastatin A (1) began with

disconnection at the amide linkage, leading to the acid side

chain 3 and the Teoc-protected N,O-aminal 4 (Scheme 1). The

acid-sensitive N,O-aminal moiety would be installed late in the

synthesis, with complete retention of conﬁguration via a Curtius

rearrangement, a strategy ﬁrst developed and successfully

exploited in our 2002 synthesis of (+)-zampanolide, bearing a

similar N,O-aminal group.¹⁵Disconnection at C(16)−C(17)

next provided aldehyde 5 and 2,6-trans-tetrahydropyran 6, which

we envisioned would be united via a substrate-controlled aldol

reaction. Aryl aldehyde 5 in turn would derive by a [4 + 2]

cycloaddition between known bis-silyl enol ether 7¹⁶and allene

8,¹⁷while 2,6-trans-tetrahydropyran 6 would arise via a 6-exo-tet-

cyclization of the C(13), hydroxyl with an epoxide that would be

installed at the C(8)−C(9). Epoxide 9 in turn would be

generated by iterative chemoselective functionalization of diene

10, a synthetic tactic that directs reactivity to the most electron-

rich oleﬁn, distal to the electron withdrawing ester group.

Synthetic strategies that selectively introduce functionality taking

advantage of the diﬀerence in electron density of the oleﬁnic

linkage along a linear polyene, possessing a terminal electron-

withdrawing group, have not, as of yet, been widely

exploited.¹⁸⁻²¹

treatment of (+)-11 with aqueous hydrochloric acid. The

primary alcohol was then protected chemoselectively as the

pivalate ester (+)-12, followed by protection of the secondary

alcohol as a SEM ether. Reduction with DIBAL-H then provided

primary alcohol (+)-13, which was oxidized via a two-step

Parikh-Doering²²/Pinnick²³oxidation sequence to provide the

desired acid side chain (−)-3.

The requisite aryl aldehyde 5 was constructed via a Diels−

Alder cycloaddition between 1,3-bis(trimethylsiloxy)-1,3-diene

7¹⁶and dimethyl-1,3-allene-dicarboxylate 8,¹⁷followed by a

ﬂuoride-mediated aromatization to furnish known homopthalate

14²⁴in 83% yield (Scheme 3). Both phenols were then masked as

SEM ethers, followed by chemoselective reduction to furnish aryl

aldehyde 5 in an overall yield of 55% for the three-step sequence.

Access to 2,6-trans-tetrahydropyran 6, the core of (+)-irci-

niastatin A (1), began with commercially available S-

epoxybutane (−)-15. Selection of (−)-15 was simply a matter

of synthetic convenience, in order to operate with a single

diastereomer, as the advanced alcohol would ultimately be

oxidized to a ketone (vide infra). Treatment of epoxide (−)-15

with propynyllithium and BF₃·OEt₂provided the homopropar-

gylic alcohol,²⁵which was protected to furnish benzyl ether

Synthesis of the requisite acid side chain (−)-3 began with

methyl ether (+)-11,³which was constructed from commercially

available (+)-isopropylidene glyceraldehyde in a stereocon-

trolled fashion in two steps; the overall yield was 57% yield (dr >

20:1 Scheme 2). Removal of the acetonide was next achieved by

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utilizing (−)-diisopropyl tartrate, furnished epoxide (+)-25 with

20:1 dr. To complete the construction of the linear precursor for

tetrahydropyran 6, alcohol (+)-25 was oxidized³²directly to the

carboxylic acid, followed by treatment with diazomethane to

provide the corresponding methyl ester in 76% yield for the two

steps. Oxidative removal of the PMB ether protecting group with

DDQ completed the construction of (+)-26, the tetrahydropyr-

an cyclization precursor. The overall yield for the 18-step

synthetic sequence was 9.3% yield.

Scheme 3. Synthesis of Dihydroisocoumarin Fragment 5

With (+)-26 in hand, we examined the acid-promoted

cyclization to generate the tetrahydropyran core. Baldwin

rules³³suggest that both the desired 6-exo-tet and undesired 7-

endo-tet cyclization pathways could operate. However, the six-

membered ring transition state, in conjunction with the electron-

withdrawing nature of the ester, destabilizing the partial cationic

character at the α-carbon under Lewis- or Brønsted- acidic

conditions, suggested that the tetrahydropyran would predom-

inate. Indeed, treatment with 20 mol % of camphorsulfonic acid

(CSA) in methylene chloride achieved the desired 6-exo-tet

cyclization pathway, which provided the 2,6-tetrahydropyran

(+)-27 in excellent yield (92%), with no trace of the seven-

membered ring congener (Scheme 6). Alcohol (+)-27 was then

methylated with dimethyl sulfate, followed by palladium-

promoted hydrogenolysis to remove the benzyl ether. Dess−

Martin periodinane³⁴oxidation completed construction of the

requisite 2,6-trans-tetrahydropyran fragment (+)-6 in 88% yield

for the three steps.

(−)-16 under acidic conditions. Next, following Negishi’s

protocol²⁶for the in situ generation of the Schwartz reagent

from zirconocene dichloride and DIBAL-H, iodination with N-

iodosuccinimide furnished the external vinyl iodide (−)-17.

Pleasingly, the regioselectivity was excellent (>20:1). Vinyl

iodide (−)-17 was then united with methyl acrylate, exploiting a

palladium-mediated Heck reaction²⁷to complete diene (−)-18

in 78% yield (Scheme 4).

Scheme 4. Synthesis of Diene (−)-18

Having constructed the three fragments for the proposed

synthesis of (+)-irciniastatin A (a.k.a. psymberin) (1), we turned

to the union of tetrahydropyran (+)-6 with aryl aldehyde 5

(Scheme 7), exploiting a substrate-controlled aldol reaction.

Generation of the Z-boron enolate of (+)-6, achieved by

treatment of (+)-6 with dichlorophenylborane,³⁵followed by

addition of aldehyde 5 furnished (+)-29, the desired syn-aldol

product, in 90% yield. The stereochemical outcome was dictated

by 1,4-substrate stereoinduction.³⁶Subsequent chelation-con-

trolled reduction³⁷followed by saponiﬁcation of the methyl ester

with concomitant lactonization provided dihydroisocoumarin

(+)-30 in 83% yield for the two steps.

At this juncture we called upon a Curtius rearrangement to

install the N,O-aminal (Scheme 7). Acid (+)-30 was converted to

the corresponding acyl azide, followed by thermal rearrangement

in toluene (ca. 80 °C) to provide the isocyanate, which was

intercepted by the addition of 2-trimethylsilylethanol to furnish

the desired N,O-aminal, with complete retention of conﬁguration

at the methyl ether carbon (NMR). Protection of the remaining

free hydroxyl group as the TBS ether was then achieved in 91%

yield to complete the construction of advanced amide (+)-4, the

coupling partner for acid side chain (−)-3.

Final fragment union of N,O-aminal (+)-4 with side chain

(−)-3 required considerable experimentation. Eventually we

discovered that deprotonation of the Teoc-protected amine

(+)-4 with LiHMDS, followed by addition of the side chain,

activated as the pivalate anhydride 31, would lead to the desired

amide (+)-32 in 79% yield (Scheme 8).

Turning our attention to conditions that would achieve global

deprotection while retaining the delicate N,O-aminal moiety,

model studies revealed that TAS-F^38,39was the reagent of choice.

Treatment of the fully protected irciniastatin A (+)-32 with TAS-

F in DMF at 50 °C resulted in two major products (Scheme 8).

After puriﬁcation via preparative TLC, the more polar of the two

congeners proved to be (+)-ircinaistatin A (1), while the less

polar compound retained one phenolic SEM group. Subjecting

Installation of the ﬁrst of the three epoxides to construct the

linear precursor of tetrahydropyran 6 entailed chemoselective

epoxidation of the most electron-rich oleﬁn in (−)-18 with the

Shi fructose-derived catalyst (−)-19²⁸to furnish (+)-20;

excellent diastereoselectivity (14:1) resulted (Scheme 5).

Regioselective opening was then achieved with trimethylalumi-

num²⁹to provide a single regioisomeric alcohol, which was

treated with PMB-Cl to furnish ether (+)-21. Asymmetric

epoxidation to introduce the second epoxide required DIBAL-H

reduction of ester (+)-21 followed by a Sharpless asymmetric

epoxidation.³⁰Epoxy alcohol (+)-22 resulted as a single

diastereomer in 92% yield for the two steps, which was then

subjected to Parikh−Doering oxidation conditions;²²the

resulting aldehyde was then treated with Horner−Wads-

worth−Emmons ylide 23 to provide ester (+)-24 in 89% yield

(two steps). Palladium-catalyzed hydrogenolysis³¹employing

formic acid as the hydrogen source next opened the epoxide in

(+)-9, again with excellent chemoselectivity. Subsequent

protection of the resulting alcohol as the TBS ether furnished

(+)-24 in 92% yield for two steps. The third and ﬁnal epoxide was

installed by reduction of ester (+)-24 with DIBAL-H to reveal

the allylic alcohol; Sharpless asymmetric epoxidation,³⁰this time

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Scheme 5. Synthesis of Pyran Precursor (+)-26

Scheme 6. Completion of Tetrahydropyran (+)-6

Scheme 7. Fragment Union and Elaboration to Amidation

Precursor

the latter to magnesium bromide⁴⁰resulted in (+)-irciniastatin A

(1), furnishing a combined yield of 74% for the two steps.

Pleasingly, the spectral data (¹H and ¹³C NMR) of totally

synthetic (+)-irciniastatin A (1) proved to be identical in all

respects with the spectra of natural (+)-irciniastatin A (1)

reported by Pettit¹and Crews.²The total synthesis of

(+)-irciniastatin A (a.k.a. psymberin) (1) had thus been achieved

with a longest linear sequence of 30 steps (ca. 2.2% overall yield).

Second-Generation Synthesis of (+)-Irciniastatin A

(a.k.a. Psymberin). Although we had achieved the total

synthesis of (+)-irciniastatin A (1) (a.k.a. psymberin),

construction of the core 2,6-trans-tetrahydropyran required 22

steps and proceeded with an overall yield of only 7.6%. To

provide material for future biological evaluation, as well as to

access a series of synthetic analogues, an improved second-

generation approach to tetrahydropyran (+)-6 would be

required. The new strategy to (+)-6 (Scheme 9) was anticipated

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single enantiomer. Mosher’s ester analysis demonstrated the

desired (R)-isomer was obtained.^42,43Alcohol (+)-34 was then

protected as the TBS ether, followed by reduction of the methyl

ester with DIBAL-H to furnish the corresponding allylic alcohol.

Asymmetric epoxidation via the Sharpless³⁰protocol next

provided the desired β-epoxide (+)-38 with 13:1 diastereose-

lectivity, which in turn was converted directly to the

corresponding acid via a one-pot TEMPO³²oxidation;

subsequent methylation led to methyl ester (+)-39.

Scheme 8. Completion of (+)-Irciniastatin A (1) (a.ka.

Psymberin)

Chemoselective deprotection of the primary TBS ether was

then achieved by treatment of (+)-39 with hydrogen ﬂuoride,

buﬀered with pyridine (Scheme 10). The resulting primary

alcohol was oxidized²²to aldehyde (+)-40, and the ﬁnal

stereocenter required for the tetrahydropyran core was

introduced via Paterson aldol union^44,45with 2-butanone,

employing (−)-B-chlorodiisopinocampheylborane (DIP-Cl) as

the chiral Lewis acid. A 5:1 (β:α) diastereomeric mixture

resulted. Cyclization employing a catalytic amount of CSA

furnished (+)-41 and (−)-42 exclusively via the 6-exo-tet

pathway, again without formation of the seven-membered ring

construct. Fortunately, the trans- and cis-diastereomers could

now be readily separated by column chromatography to yield

2,6-trans-tetrahydropyran (+)-41 in 74% yield for the 2 steps.

Methylation of the secondary hydroxyl group was achieved (92%

yield) by treatment with Me₃O·BF₄and proton sponge [1,8-

bis(dimethylamino)naphthalene] to complete the second-

generation synthesis of the 2,6-trans-tetrahydropyran core

(+)-6. Pleasingly, the new route to (+)-6 proceeded with a

longest linear sequence of 13 steps (a 9-step improvement) and

with an overall yield of 17.8% yield, thus more than doubling the

overall yield for the longest linear sequence compared to the ﬁrst-

generation synthesis.

Total Synthesis of (−)-Irciniastatin B. With an eﬀective

route to (+)-irciniastatin A (1), and an improved route to the

common tetrahydropyran core, we turned to the construction

the biologically more active congener, (−)-irciniastatin B (2). To

achieve the requisite ketone oxidation state at C(11), the C(15)

secondary hydroxyl in (+)-43, a late-stage intermediate

employed in our synthesis of (+)-irciniastatin A (1),⁹was

envisioned to be protected as a SEM ether, instead of the TBS

ether employed earlier (Scheme 11). This protecting group was

selected to permit the critical, selective deprotection of the

neopentyl secondary TBS ether at C(11). The secondary alcohol

would be oxidized to the requisite ketone, followed by global

deprotection to provide access to (−)-irciniastatin B (2).

Chemical modiﬁcation of the late stage C(11) ketone would

also permit access to a series of analogues possessing varying

substitution at C(11), thus enabling a structure activity

relationship study (SAR) to be carried out at this key center in

the irciniastatin chemotype.

Scheme 9. Revised Retrosynthetic Strategy of

Tetrahydropyran (+)-6

to retain the eﬃcient 6-exo-tet cyclization of acyclic epoxide

precursor 33, which would be constructed via two reagent-

controlled asymmetric transformations from alcohol 34, that in

turn would derive via union of aldehyde 35 and ketene acetal 36,

exploiting a vinylogous Mukayaima aldol reaction.⁴¹In this

strategy, the gem-dimethyl moiety would arise from commer-

cially available 2,2-dimethyl-1,3-propanediol, instead of the

epoxide opening strategy employed in our ﬁrst-generation

synthesis. Importantly, the second-generation route would set

the requisite stereogenecity in tetrahydropyran (+)-6 via three

reagent-controlled asymmetric reactions.

We began the second-generation synthesis of (+)-6 via

monoprotection of commercially available 2,2-dimethyl-1,3-

propanediol 37 (Scheme 10), followed by oxidation of the

second hydroxyl employing the Parikh−Doering²²protocol to

provide aldehyde 35. Treatment of aldehyde 35 and ketene acetal

36⁴¹employing the chiral oxazaborolidinone derived from L-

tryptophan led to a vinylogous Mukaiyama aldol reaction,⁴¹

thereby installing the ﬁrst stereocenter to furnish (+)-34 as a

Surprisingly, protection of the C(15) hydroxyl group in (+)-43

as the SEM ether proved particularly challenging. In particular,

manipulation of the resultant SEM ether during workup and

puriﬁcation routinely resulted in the unanticipated loss of the

phenolic SEM ethers. Attempts at reprotection proved

ineﬀective, even at elevated temperatures. After extensive

experimentation with several model systems, we discovered

that the phenolic 3,4-dimethoxybenzyl ether (DMB) would

prove durable in the late-stage synthetic sequence with the

orthogonally protected C(11) TBS ether.

Synthesis of the revised aryl fragment 45 thus began with

protection of bis-phenol 14²⁴with DMB-Br (Scheme 12).

Reduction of the resulting ester with DIBAL-H furnished the aryl

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Scheme 10. Second-Generation Synthetic Route towards Tetrahydropyran (+)-6

in hand, the corresponding acyl azide was generated and

subjected to the conditions for the Curtius rearrangement¹⁵to

furnish the Teoc-protected N,O-aminal in 67% yield, again with

complete retention of stereochemical conﬁguration at C(8). The

resulting secondary alcohol was then protected as the SEM ether

(+)-48 in 82% yield. Importantly, workup and/or puriﬁcation

proceeded without the formation of undesired side products,

compared to the earlier SEM protection strategy.

Scheme 11. Divergent Strategy Toward the Synthesis of

(−)-Irciniastatin B

Achieving the requisite amide union to provide (+)-50 once

again proved challenging (Scheme 13). The conditions

employed in our earlier (+)-irciniastatin A (1) synthesis,⁹

involving LiHMDS as the base with the mixed anhydride 31,

resulted in low yields (ca. 15%). After signiﬁcant screening, the

conditions employed by Crimmins and co-workers¹⁰in their

synthesis of (+)-irciniastatin A (1), namely, the use of i-PrMgCl

as the base and acid chloride 49, provided the desired amide

(+)-50 in 72% yield.

Having arrived at the full carbon skeleton of (−)-irciniastatin B

(2), we set out to eﬀect selective deprotection of the hindered

neopentyl secondary C(11) TBS ether (Scheme 13). The TBS

ether (+)-50 was treated with TBAF at room temperature, which

resulted in hydrolysis of the Teoc carbamate. Subsequent

warming the reaction mixture to 50 °C then led to selective

removal of the C(11) TBS group in an overall yield of 79%.

Oxidation with Dess−Martin periodinane³⁴provided ketone

(−)-51.

aldehyde 45. From here, the synthetic route continued in similar

fashion to the sequence leading to (+)-irciniastatin A (1).⁹Aldol

union³⁵between aldehyde 45 and ketone (+)-6 pleasingly

furnished β-hydroxyketone (+)-46 in 70% yield, with minor

concomitant lactonization (10:1) and excellent diastereoselec-

tivity (>20:1).³⁶Chelation-controlled reduction³⁷resulted in a

mixture of the desired syn diol and the corresponding lactone (ca.

8:1). The mixture was treated under saponiﬁcation conditions to

provide acid (+)-47 in 69% yield for the 2 steps. With acid (+)-47

In order to remove the two pairs of protecting groups in

(−)-51 and complete the synthesis of (2), a two-stage

deprotection protocol was required. Introduction of the ketone

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did provide the desired bis-phenol without observable

decomposition. Removal of the two remaining SEM groups

with either TAS-F^38,39or TBAF, however, resulted only in

complex mixtures, highlighting the base sensitivity of ketone

(−)-51. Again, after signiﬁcant experimentation, we discovered

that treatment of the bis-phenol with a premixed solution of

MgBr₂, n-butanethiol, and nitromethane in ether⁴⁸removed the

SEM ethers cleanly to provide (−)-irciniastatin B (2) in 78%

yield for the two steps. Pleasingly, synthetic (−)-irciniastatin B

(2) proved to be identical in all regards (¹H and ¹³C NMR) with

the spectral data obtained by Pettit and co-workers¹and thus

constituted the ﬁrst total synthesis of (−)-irciniastatin B (2).

In order to verify the structural relationship of (−)-irciniastatin

B (2) with (+)-irciniastatin A (1), we carried out a chemical

interconversion of (2) to (1) (Scheme 14). To this end, 2 was

Scheme 12. Synthesis of N,O-Aminal (+)-48

Scheme 14. Structural Conﬁrmation of (−)-Irciniastatin B (2)

by Chemical Conversion to (+)-Irciniastatin A (1) (a.k.a.

Psymberin)

moiety in the tetrahydropyran, however, greatly enhances the

sensitivity of the molecular structure. For example, treatment of

(−)-51 with base readily initiates a retro-Michael/Michael

addition, eﬀecting epimerization of C(9) of the tetrahydropyran

core,⁴⁶while acid treatment results in hydrolysis of the N,O-

aminal.⁴⁷Fortunately, treatment of ketone (−)-51 with DDQ

Scheme 13. Completion of (−)-Irciniastatin B (2)

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Diol (+)-53 (0.243 g, 1.52 mmol) in pyridine (4 mL) was cooled to 0

°C, followed by addition of trimethylacetyl chloride (0.205 mL, 1.67

mmol). The reaction was allowed to warm to rt, and after 1 h, the

reaction was cooled to 0 °C, and H₂O (5 mL) was added. The reaction

was diluted with Et₂O (5 mL) and washed successively with 5 mL each

of sat. NaHCO₃, 1 N HCl, and brine. The organic layer was then dried

over MgSO₄and concentrated. Flash chromatography (10% EtOAc/

hexanes) provided (+)-12 (0.325 g, 88% yield) as colorless oil: [α]_D²⁰

+23.9 (c 1.1, CHCl₃); IR (neat) 3467, 2971, 2935, 1728, 1457, 1286,

1163, 1103 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 4.84 (s, 1H), 4.81 (s,

1H), 4.23 (dd, J = 11.7, 3.5 Hz, 1H), 4.16 (dd, J = 11.6, 6.8 Hz, 1H),

3.92−3.82 (m, 1H), 3.48−3.39 (m, 1H), 3.40 (s, 3H), 2.39 (d, J = 4.8

Hz, 1H), 2.29 (ddd, J = 19.4, 14.4, 6.2 Hz, 2H), 1.79 (s, 3H), 1.22 (s,

9H); ¹³C NMR (125 MHz, CDCl₃) δ 179.0, 142.6, 113.3, 80.6, 71.4,

65.6, 58.4, 39.0, 38.4, 27.4, 23.0; high resolution mass spectrum (ES+)

m/z 245.1743 [(M + H)⁺; calcd for C₁₃H₂₅O₄245.1753].

Alcohol (+)-13. A solution of (+)-12 (0.221 g, 0.905 mmol) in

CH₂Cl₂(3 mL) was cooled to 0 °C, and i-Pr₂NEt (0.395 mL, 2.5 equiv)

was added, followed by dropwise addition of SEMCl (0.320 mL, 2.0

equiv). The reaction was allowed to warm to rt, and after 2 h, sat. NH₄Cl

was added. The reaction was extracted with CH₂Cl₂(3 × 10 mL), and

the combined organic layers were dried over MgSO₄and concentrated.

Flash chromatography (5% EtOAc/hexanes) provided SEM ether

(−)-54 (338 mg, 99% yield) as colorless oil: [α]²_D⁰−6.3 (c 2.9, CHCl₃);

IR (neat) 3457, 2925, 1728, 1480, 1283, 1249, 1159, 1107, 1031 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 4.81 (s, 1H), 4.78 (s, 1H), 4.74 (dd, J =

14.7, 6.9 Hz, 2H), 4.29 (dd, J = 11.8, 3.9 Hz, 1H), 4.11 (dd, J = 11.8, 6.2

Hz, 1H), 3.84−3.79 (m, 1H), 3.68 (ddd, J = 10.1, 6.3, 6.3 Hz, 1H), 3.59

(ddd, J = 10.0, 6.5, 6.5 Hz, 1H), 3.51−3.46 (m, 1H), 3.39 (s, 3H), 2.32−

2.19 (m, 2H), 1.77 (s, 3H), 1.19 (s, 9H) 0.99−0.82 (m, 2H), 0.00 (s,

9H); ¹³C NMR (125 MHz, CDCl₃) δ 178.4, 142.7, 113.0, 95.0, 80.3,

76.8, 65.6, 64.0, 58.6, 39.4, 39.0, 27.4, 23.0, 18.2, −1.2; high resolution

mass spectrum (ES+) m/z 397.2372 [(M + Na)⁺; calcd for

C₁₉H₃₈O₅SiNa 397.2387].

A solution of SEM ether (−)-54 (0.339g, 0.905 mmol) in CH₂Cl₂

(4.5 mL) was cooled to −78 °C, and DIBAL-H (2.0 mL, 1 M in toluene,

2.2 equiv) was added dropwise. After 5 min, the reaction was quenched

with MeOH (0.5 mL). The reaction was allowed to warm to rt before

EtOAc (5 mL) and sat. Rochelle’s salt (5 mL) were added. After 1 h, the

organic layer transitioned from cloudy to clear. The layers were

separated, and the aqueous layer extracted with EtOAc (3 × 10 mL).

The combined organic layers were dried over MgSO₄and concentrated.

Flash chromatography (10% EtOAc/hexanes) provided (+)-13 (0.249

g, 95% yield) as colorless oil: [α]²_D⁰+31.7 (c 1.2, CHCl₃); IR (neat) 3457,

2952, 2925, 2892, 1650, 1457, 1378, 1249, 1102, 1054, 1025 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ 4.82 (s, 1H), 4.78 (s, 1H), 4.76 (dd, J = 14.3,

7.0 Hz, 2H), 3.79−3.68 (m, 3H), 3.65−3.56 (m, 2H), 3.49 (ddd, J = 7.6,

4.8, 4.8 Hz, 1H), 3.41 (s, 3H), 3.21 (dd, J = 8.3, 4.2 Hz, 1H), 2.31 (dd, J =

14.4, 7.6 Hz, 1H), 2.21 (dd, J = 14.4, 5.3 Hz, 1H), 1.77 (s, 3H), 0.99−

0.92 (m, 2H), 0.02 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 142.6,

113.2, 95.6, 82.6, 81.0, 66.0, 62.7, 58.6, 39.5, 23.0, 18.3, −1.3; high

resolution mass spectrum (ES+) m/z 313.1821 [(M + Na)⁺; calcd for

C₁₄H₃₀O₄SiNa 313.1811].

Acid (−)-3. A solution of (+)-13 (0.117 g, 0.404 mmol) in DMSO

(0.29 mL, 10 equiv) and CH₂Cl₂(4 mL) was cooled to 0 °C, and i-

Pr₂NEt (0.212 mL, 3 equiv) was added followed by SO₃·pyridine (0.193

g, 3 equiv) in one portion. After 5 min, brine (10 mL) and H₂O (2 mL)

were added, and the reaction was warmed to rt. The layers were

separated, and the aqueous layer was extracted with CH₂Cl₂(3 × 10

mL). The combined organic layers were dried over MgSO₄and

concentrated. Flash chromatography (5% EtOAc/hexanes) provided

aldehyde (−)-55 (0.113 g, 97%) as a colorless oil: [α]²_D⁰−9.1 (c 0.9,

CHCl₃); IR (neat) 2952, 2892, 2825, 1732, 1450, 1376, 1249, 1108,

1060, 1029 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 9.66 (d, J = 1.4 Hz,

1H), 4.85 (s, 1H), 4.84 (s, 1H), 4.80 (dd, J = 19.4, 6.9 Hz, 2H), 4.11 (dd,

J = 2.8, 1.5 Hz, 1H), 3.75−3.69 (m, 2H), 3.65 (ddd, J = 9.8, 9.8, 6.9 Hz,

1H), 3.41 (s, 3H), 2.33 (dddd, J = 14.1, 14.1, 14.1, 6.9 Hz, 2H), 1.72 (s,

3H), 0.92 (ddd, J = 10.1, 6.6, 3.3 Hz, 2H), 0.02 (s, 9H); ¹³C NMR (125

MHz, CDCl₃) δ 202.4, 141.7, 114.4, 96.3, 82.5, 81.8, 66.1, 58.1, 38.9,

treated with NaBH₄, which resulted in a mixture (1:1) of

(+)-irciniastatin A 1 and epi-C(11)-irciniastatin A (52). The two

diastereomers were separated via preparative TLC, and the

spectral data of the faster moving diastereomer (TLC) was

identical with the spectral data of (+)-irciniastatin A (i.e., ¹H, ¹³C

NMR and HRMS), thereby conﬁrming the structural relation-

ship of (+)-irciniastatin A (1) and (−)-irciniastatin B (2).

SUMMARY

■

The evolution of an eﬀective uniﬁed synthetic strategy for the

construction (+)-irciniastatin A (1) (a.k.a. psymberin) and

(−)-irciniastatin B (2) has been achieved. The ﬁrst-generation

synthesis of (+)-ircinastatin A required 30 steps and proceeded

in 2.2% overall yield. Of these 30 steps, 22 were required to

construct the 2,6-trans-tetrahydropyran, which proceeded in

7.6% overall yield. A signiﬁcantly improved second-generation

synthesis of the 2,6-trans-tetrahydropyran core was subsequently

achieved, which now permits an eﬃcient total synthesis of both

(+)-irciniastatin A (1) and (−)-irciniastatin B (2), the latter

requiring a chemoselective deprotection/oxidation sequence.

Finally, the structural relationship of the two similar metabolites

has been conﬁrmed via chemical conversion of (−)-irciniastatin

B (2) to (+)-irciniastatin A (1) and the corresponding C(11)

epimer (52). Importantly, the successful synthesis leading to

(−)-irciniastatin B (2) now holds the promise for the elaboration

of C(11)-irciniastatin analogues, currently ongoing in our

laboratory.

EXPERIMENTAL SECTION

■

Materials and Methods. Reactions were carried out in ﬂame-dried

or oven-dried glassware under a nitrogen atmosphere unless noted

otherwise. Anhydrous diethyl ether (Et₂O), tetrahydrofuran (THF),

dichloromethane (CH₂Cl₂) and toluene were obtained from a solvent

puriﬁcation system. All commercially available reagents were used

without puriﬁcation unless otherwise noted. Triethylamine, diisopro-

pylethylamine, and pyridine were freshly distilled from calcium hydride

under a nitrogen atmosphere. Reactions were magnetically stirred unless

stated otherwise and monitored by thin layer chromatography (TLC)

with 0.25 mm Silacycle precoated silica gel plates. Silica gel

chromatography was performed utilizing ACS grade solvents and silica

gel from either Silacycle or Sorbent Technologies.

Infrared spectra were obtained using an FT/IR spectrometer. Optical

rotations were obtained using a polarimeter. All melting points were

1

obtained on a melting point apparatus and are uncorrected. H NMR

spectra (500 MHz ﬁeld strength) and ¹³C NMR spectra (125 MHz ﬁeld

strength) were obtained on 500 MHz spectrometer or a cryomagnet

(500 MHz/52 mm) with a 5 mm dual cryoprobe. Chemical shifts are

1

reported relative to chloroform (δ 7.26) or methanol (δ 4.78) for H

NMR spectra and chloroform (δ 77.23), methanol (δ 49.3), or benzene

(δ 128.0) for ¹³C spectra. High-resolution mass spectra (HRMS) were

measured on an LC-TOF mass spectrometer

Pivalate Ester (+)-12. A 2 N HCl solution (10 mL) was added to

acetonide (+)-11 (0.836 g, 4.18 mmol) at rt. After 30 min, the reaction

was quenched with sat. NaHCO₃until all gas evolution had ceased. The

reaction was then extracted with EtOAc, and the combined organic

layers were dried over MgSO₄and concentrated. Flash chromatography

(40% EtOAc/hexanes) provided diol (+)-53 (0.650 g, 97% yield) as a

colorless oil: [α]²_D⁰+21.8 (c 1.5, CHCl₃); IR (neat) 3416, 2932, 1646,

1456, 1092, 1050 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 4.84 (q, J = 1.6

Hz, 1H), 4.80 (m, 1H), 3.82−3.77 (m, 1H), 3.72−3.67 (m, 2H), 3.57−

3.53 (ddd, J = 2.4, 6.5, 13.1 Hz, 1H), 3.43 (s, 3H), 2.61 (d, J = 6.7 Hz,

1H), 2.39 (dd, J = 14.0, 6.8 Hz, 1H), 2.32 (dd, J = 7.2, 3.2 Hz, 1 H), 2.18

(dd, J = 14.3, 6.4 Hz, 1H), 1.79 (ap t, J = 1.1 Hz, 3H); ¹³C NMR (125

MHz, CDCl₃) δ 142.49, 113.2, 81.7, 72.8, 63.3, 58.4, 38.9, 22.9; high

resolution mass spectrum (CI+) m/z 161.1177 [(M + H)⁺; calcd for

C₈H₁₇O₃161.1178].

H

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22.8, 18.2, 1.2; high resolution mass spectrum (ES+) m/z 311.1666 [(M

+ Na)⁺; calcd for C₁₄H₂₈O₄SiNa 311.1655].

Hz, 3H), 1.64−1.48 (m, 2H), 0.94 (dd, J = 7.5, 7.5 Hz, 3H); ¹³C NMR

(125 MHz, CDCl₃) δ 78.3, 75.5, 71.7, 29.2, 27.3, 10.1, 3.6; low

resolution mass spectrum (ES+) m/z 112.10 [(M + )⁺; calcd for C₇H₁₂O

112.0888].

Aldehyde (−)-55 (0.203 g, 0.704 mmol) was dissolved in t-BuOH

(7.5 mL) and H₂O (7.5 mL). The solution was cooled to 0 °C followed

by addition of 2-methyl-2-butene (6 mL), NaH₂PO₄·H₂O (0.550 g, 5

equiv), and NaClO₂(0.483 g, 80 wt %, 5 equiv). After 15 min, the

reaction was poured onto sat. NH₄Cl (10 mL) and extracted thoroughly

with EtOAc. The combined organic layers were dried over MgSO₄and

concentrated. Flash chromatography (25% EtOAc/hexanes to 40%

EtOAc/hexanes) provided (−)-3 (0.196 g, 92% yield) as a colorless oil:

[α]²_D⁰−18.6 (c 1.1, CHCl₃); IR (neat) 2953, 2925, 1725, 1649, 1376,

1252, 1110, 1060, 1030 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 4.83 (s,

1H), 4.81 (s, 1H), 4.78 (s, 2H), 4.39 (d, J = 3.1 Hz, 1H), 3.75 (ddd, J =

8.2, 5.2, 3.2 Hz, 1H), 3.68 (dd, J = 8.5, 8.5 Hz, 2H), 3.43 (s, 3H), 2.39

(dd, J = 14.6, 8.0 Hz, 1H), 2.28 (dd, J = 14.6, 5.2 Hz, 1H), 1.76 (s, 3H),

0.96−0.87 (m, 2H), 0.01 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 175.0,

141.9, 113.5, 95.1, 81.0, 76.2, 66.3, 58.3, 38.7, 22.9, 18.2, −1.3; high

resolution mass spectrum (ES+) m/z 327.1614 [(M + Na)⁺; calcd for

C₁₄H₂₈O₅SiNa 327.1604].

Aldehyde 5. A solution of homophthalate 14 (0.305 g, 1.20 mmol)

in THF (6 mL) was cooled to 0 °C, and NaH (0.106 g, 60 wt %, 2.2

equiv) was added. After 5 min, SEMCl (0.53 mL, 2.5 equiv) was added

dropwise. The reaction was allowed to warm to rt, and after 30 min the

reaction was quenched with slow addition of MeOH (0.5 mL). Sat.

NaHCO₃(5 mL) was added, and the reaction was extracted with

CH₂Cl₂(3 × 10 mL). The combined organic layers were then dried over

MgSO₄and concentrated. Flash chromatography (10% EtOAc/

hexanes) provided bis-SEM ether 56 (0.611 g, 99% yield) as a colorless

oil: IR (neat) 2952, 2898, 1736, 1597, 1314, 1266, 1250, 1158, 1067

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 6.94 (s, 1H), 5.22 (s, 2H), 5.17 (s,

2H), 3.85 (s, 3H), 3.77−3.69 (m, 4H), 3.67 (s, 5H), 2.12 (s, 3H), 0.98−

0.91 (m, 4H), 0.00 (s, 9H), 0.00 (s, 9H); ¹³C NMR (125 MHz, CDCl₃)

δ 171.1, 168.6, 157.4, 153.8, 132.3, 120.7, 119.0, 101.9, 94.0, 93.4, 66.5,

66.5, 52.2, 52.2, 36.3, 18.3, 18.2, 11.7, −1.2; high resolution mass

spectrum (ES+) m/z 537.2303 [(M + Na)⁺; calcd for C₂₄H₄₂O₈Si₂Na

537.2316].

A solution of bis-SEM ether 56 (0.104 g, 0.202 mmol) in CH₂Cl₂(2.0

mL) was cooled to −78 °C, and DIBAL-H (0.22 mL, 1 M solution in

toluene, 1.1 equiv) was added dropwise over 15 min. After 5 min, the

reaction was quenched with MeOH. The reaction was allowed to warm

to rt before EtOAc (5 mL) and sat. Rochelle’s salt (5 mL) were added.

After 1 h, the organic layer transitioned from cloudy to clear. The layers

were separated, and the aqueous layer extracted with 3 × 20 mL EtOAc.

The combined organic layers were dried over MgSO₄and concentrated.

Flash chromatography (10% EtOAc/hexanes) provided 5 (0.64 g, 66%

yield) as a light yellow oil: IR (neat) 2953, 2901, 1726, 1595, 1477, 1272,

1251, 1157, 1110, 1065 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) 9.62 (dd, J =

1.8, 1.8 Hz, 1H), 6.97 (s, 1H), 5.24 (s, 2H), 5.19 (s, 2H), 3.85 (s, 3H),

3.79−3.71 (m, 4H), 3.64 (d, J = 1.8 Hz, 2H), 2.08 (s, 3H), 0.99−0.91

(m, 4H), 0.00 (s, 9H), 0.00 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ

198.7, 168.7, 157.7, 154.0, 130.5, 120.8, 119.3, 102.1, 93.9, 93.4, 66.6,

66.6, 52.3, 46.1, 18.3, 18.2, 11.9, −1.2; high resolution mass spectrum

(ES+) m/z 507.2210 [(M + Na)⁺; calcd for C₂₃H₄₀O₇Si₂Na 507.2211].

Alkyne (−)-16. To solution of THF (600 mL), cooled to −78 °C,

was added propyne (100 g, 4 equiv) via subsurface cannula to dissolve

the gas in the THF. Next, a solution of n-BuLi (570 mL, 2.2 M in

hexanes, 2 equiv) was cooled to −78 °C and added to the propyne

solution over 1 h via cannula. After stirring for 1.5 h at −78 °C (S)-1,2-

epoxybutane [(−)-15] (45 g, 0.625 mol) was added via cannula over 25

min followed by addition of BF₃·OEt₂over 45 min via cannula. After

stirring for 1.5 h at −78 °C, the reaction was quenched with sat.

NaHCO₃until all gas evolution ceased (ca. 3 h). The layers were

separated, and the aqueous layer extracted with Et₂O (3 × 500 mL). The

combined organic layers were dried over MgSO₄and concentrated in a 0

°C bath (to minimize loss of product due to slight volatility) to provide

alcohol (+)-57 (55.6 g, 79%) as a colorless oil: [α]²_D⁰+11.0 (c 1.3,

CHCl₃); IR (neat) 3382, 2964, 2922, 1461, 1435, 1335, 1245, 1112,

1063, 1020 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 3.69−3.55 (m, 1H),

2.37 (ddddd, J = 16.4, 4.9, 2.5, 2.5, 2.5 Hz, 1H), 2.24 (ddddd, J = 16.4,

7.2, 2.5, 2.5, 2.5 Hz, 1H), 1.95 (d, J = 4.8 Hz, 1H), 1.80 (dd, J = 2.5, 2.5

To a solution of alcohol (+)-57 (18.5 g, 0.165 mol) in CH₂Cl₂(184

mL) and cyclohexane (368 mL) at rt was added benzyl-2,2,2-

trichloroacetimidate (50.0 g, 1.2 equiv) followed by dropwise addition

of TfOH (0.73 mL, 0.05 equiv) The solution turned cloudy and light

brown as the reaction progressed. After 6 h, hexane (600 mL) was

added, and the solution stirred 30 min to precipitate solids, and then the

suspension was ﬁltered. The ﬁltrate was washed with sat. NaHCO₃(200

mL), which was then back extracted with CH₂Cl₂(3 × 100 mL). The

combined organic layers were then dried over MgSO₄and concentrated.

The concentrate was diluted with 10% EtOAc/hexanes (200 mL) to

facilitate further precipitation of solids and then ﬁltered. The ﬁltrate was

then concentrated and puriﬁed by ﬂash chromatography (0.5% EtOAc/

hexanes to 1% EtOAc/hexanes) to provide alkyne (−)-16 (30.4 g, 91%

yield) as a light yellow oil: [α]²_D⁰−27.6 (c 1.4, CHCl₃); IR (neat) 2964,

2919, 2873, 1496, 1454, 1348, 1207, 1108, 1071, 1028 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ 7.44−7.22 (m, 5H), 4.68 (dab, J = 11.9 Hz, 1H),

4.57 (dab, J = 11.8 Hz, 1H), 3.45 (dddd, J = 6.7, 6.7, 5.1, 5.1 Hz, 1H),

2.45 (ddddd, J = 16.5, 5.1, 2.5, 2.5, 2.5 Hz, 1H), 2.41−2.32 (m, 2H), 1.81

(dd, J = 2.5, 2.5 Hz, 3H), 1.77−1.60 (m, 2H), 0.97 (dd, J = 7.4, 7.4 Hz,

3H); ¹³C NMR (125 MHz, CDCl₃) δ 138.9, 128.5, 127.9, 127.7, 79.1,

77.2, 76.1, 71.4, 26.8, 23.8, 9.8, 3.7; high resolution mass spectrum (ES

+) m/z 202.1354 [(M)⁺; calcd for C₁₄H₁₉O 202.1358].

Vinyl Iodide (−)-17. To a ﬂask protected from light was added

bis(cyclopentadienyl) zirconium(IV) chloride (0.313 g, 2.0 equiv) and

THF (1 mL). The solution was cooled to 0 °C, and DIBAL-H (1.07 mL,

1 M in hexanes, 2.0 equiv) was added dropwise. After 30 min at 0 °C,

alkyne (−)-16 (0.108g, 0.534 mmol) was dissolved in THF (0.3 mL)

and added to the in situ generated Schwartz reagent. The ﬂask and

syringe were then ﬂushed with THF (0.3 mL) into the reaction. The

reaction ﬂask was then placed in a 50 °C oil bath. After 1 h, the reaction

was cooled to 0 °C, and N-iodosuccinimide (0.265 g, 2.2 equiv) was

added. After 10 min, the reaction was quenched with sat. NaHCO₃(10

mL) and then ﬁltered through a 1 cm plug of silica gel. The silica gel was

rinsed with EtOAc, and the layers separated. The aqueous layer was then

extracted with EtOAc (3 × 10 mL), and the combined organic layers

were dried over MgSO₄and concentrated. Flash chromatography (10%

EtOAc/hexanes) provided vinyl iodide (−)-17 (135 mg, 77% yield,

>20:1 selectivity) as a colorless oil: [α]²_D⁰−4.4 (c 1.0, CHCl₃); IR (neat)

3030, 2963, 2931, 2872, 1454, 1351, 1092, 1065, 1028 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ 7.42−7.27 (m, 5H), 6.24 (dd, J = 7.5, 6.8 Hz, 1H),

4.54 (s, 2H), 3.37 (dddd, J = 5.9, 5.9, 5.9, 5.9 Hz, 1H), 2.39 (s, 3H),

2.36−2.17 (m, 2H), 1.62−1.52 (m, 2H), 0.95 (dd, J = 7.4, 7.4 Hz, 3H).;

¹³C NMR (125 MHz, CDCl₃) δ 138.9, 137.7, 128.6, 127.9, 127.7, 95.3,

79.3, 71.4, 34.8, 27.9, 26.8, 9.9.; high resolution mass spectrum (ES+)

m/z 353.0386 [(M + Na)⁺; calcd for C₁₄H₁₉IONa 353.0378].

Diene (−)-18. Vinyl iodide (−)-17 (6.02 g, 18.2 mmol) was

dissolved in anhydrous DMF (70 mL) in a sealable tube. Methyl acrylate

(2.35 g, 1.5 equiv) was added followed by Pd(OAc)₂(0.817 g, 0.20

equiv), NaHCO₃(3.06 g, 2.0 equiv), and Bu₄NI (6.73 g, 1.0 equiv). The

tube was ﬂushed with argon, sealed, and heated to 100 °C over 1 h. After

7 h at 100 °C, the reaction was cooled to 0 °C, and sat. NH₄Cl (100 mL)

added. The reaction was then ﬁltered and extracted with EtOAc (3 ×

100 mL). The combined organic layers were washed with H₂O, sat.

NaHCO₃, and brine (100 mL each). The organic layer was then dried

over MgSO₄and concentrated. Flash chromatography (3% EtOAc/

hexanes to 5% EtOAc/hexanes to 8% EtOAc/hexanes) provided diene

(−)-18 (4.11 g, 78% yield) as a light yellow oil: [α]²_D⁰−11.7 (c 1.0,

CHCl₃); IR (neat) 3033, 2963, 2873, 1719, 1624, 1310, 1194, 1169,

1123, 1097 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.34−7.26 (m, 5H),

5.97 (dd, J = 8.0, 8.0 Hz, 1 H), 5.81 (d, J = 15.5 Hz, 1H), 4.53 (s, 3H),

3.77 (s, 3H), 3.47 (ddd, J = 12.0, 6.0, 6.0 Hz, 1H), 2.51−2.43 (m, 2H),

1.78 (s, 3H), 1.57−1.64 (m, 3H), 0.94 (dd, J = 7.5, 7.5 Hz, 3H); ¹³C

NMR (125 MHz, CDCl₃) δ 168.2, 149.9, 138.9, 138.4, 134.3, 128.6,

127.9, 127.8, 115.6, 79.8, 71.4, 51.7, 33.3, 27.0, 12.6, 9.9; high resolution

mass spectrum (ES+) m/z 289.1823 [(M + H)⁺; calcd for C₁₈H₂₅O₃

289.1804].

I

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Epoxide (+)-20. Diene (−)-18 (2.94 g, 10.2 mmol) was dissolved in

CH₃CN (460 mL). Na₂B₄O₇buﬀer (0.05 M, 115 mL) was added

followed Bu₄NHSO₄(0.425 g) and ketone catalyst (−)-19 (1.32 g, 0.50

equiv). Oxone (8.77g, 1.4 equiv) was dissolved in Na₂EDTA buﬀer (59

mL, 4 × 10⁻⁴M), and K₂CO₃(8.31 g, 5.9 equiv) was dissolved in H₂O

(59 mL). The two solutions were then added simultaneously over 3 h via

a dual-syringe pump. After the addition was complete, water was added

to dissolve any solids that had formed, and the reaction extracted with

EtOAc (3 × 300 mL). The combined organic layers were washed with

brine (200 mL), dried over MgSO₄, and concentrated. Flash

chromatography (5% EtOAc/hexanes to 8% EtOAc/hexanes) provided

separated. The aqueous layer was extracted with CH₂Cl₂(3 × 20 mL),

and the combined organic layers were dried over MgSO₄and then

concentrated. Flash chromatography (25% EtOAc/hexanes) provided

allylic alcohol (+)-59 (1.56 g, 95%) as a colorless oil: [α]²_D⁰+65.0 (c 1.0,

CHCl₃); IR (neat) 3425, 2961, 2931, 2873, 1613, 1513, 1464, 1248,

1087, 1063, 1035 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.41−7.26 (m,

5H), 7.20 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.77 (d, J = 15.8

Hz, 1H), 5.60 (ddd, J = 15.8, 5.9, 5.9 Hz, 1H), 4.60 (dab, J = 11.6 Hz,

1H), 4.46 (dab, J = 10.8 Hz, 1H), 4.34 (dd, J = 2.6, 10.9 Hz, 2H), 4.10

(dd, J = 5.8, 5.8 Hz, 2H), 3.79 (s, 3H), 3.58 (ddd, J = 6.5, 4.2, 2.3 Hz,

1H), 3.40 (dd, J = 10.0, 1.5 Hz, 1H), 1.74−1.53 (m, 3H), 1.48 (ddd, J =

14.5, 10.0, 2.2 Hz, 1H), 1.07 (s, 3H), 1.06 (s, 3H), 0.90 (dd, J = 7.5, 7.5

Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 159.2, 140.6, 139.3, 131.6,

129.2, 128.6, 127.9, 127.7, 126.5, 113.9, 83.6, 77.2, 74.9, 70.0, 64.4, 55.5,

41.7, 36.5, 26.3, 24.5, 23.8, 9.3; high resolution mass spectrum (ES+) m/

z 435.2514 [(M + Na)⁺; calcd for C₂₆H₃₆O₄Na 435.2512].

To freshly activated 3 Å molecular sieves (0.2 g) in CH₂Cl₂(2 mL)

was added (+)-DIPT (31.8 μL, 0.12 equiv). The solution was cooled to

−20 °C, and Ti(O-i-Pr)₄(37.3 μL, 0.1 equiv) was added followed by t-

BuOOH (0.687 mL, 5.5 M in decane, 3.0 equiv). The reaction was

stirred for 30 min, and then allylic alcohol (+)-59 (0.521 g, 1.26 mmol)

dissolved in CH₂Cl₂(1.5 mL) was added via syringe. The ﬂask and

syringe were rinsed with CH₂Cl₂(2 × 0.8 mL) into the reaction ﬂask.

After 2 h, 10% aq. citric acid (10 mL) was added, and the reaction

warmed to rt. After 1 h at rt, the reaction was ﬁltered through Celite, and

the Celite washed with CH₂Cl₂(10 mL). The layers were separated, and

the aqueous layer extracted with CH₂Cl₂(3 × 5 mL). The combined

organic layers were dried over MgSO₄and concentrated. Flash

chromatography (25% EtOAc/hexanes) provided epoxy alcohol

(+)-22 (0.524 g, 97% yield, dr > 20:1) as a colorless oil: [α]²_D⁰+56.9

(c 0.8, CHCl₃); IR (neat) 3435, 2964, 2932, 2874, 1612, 1514, 1455,

1248, 1088, 1064, 1034 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.40−7.26

(m, 5H), 7.19 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.62 (dab, J =

11.6 Hz, 1H), 4.46 (dab, J = 11.0 Hz, 1H) 4.35 (dd, J = 11.4, 11.8 Hz,

2H), 3.85−3.80 (m, 1H), 3.79 (s, 3H), 3.63−3.52 (m, 2H), 3.52 (dd, J =

10.0, 1.4 Hz, 1H), 3.05 (dd, J = 4.8, 2.6 Hz, 1H), 2.94 (d, J = 2.4 Hz, 1H),

1.82−1.50 (m, 4H), 0.93 (s, 3H), 0.93 (dd, J = 7.6, 7.6 Hz, 3H), 0.87 (s,

3H); ¹³C NMR (125 MHz, CDCl₃) δ 159.2, 139.2, 131.4, 128.9, 128.6,

128.0, 127.7, 113.9, 82.4, 77.0, 74.6, 70.0, 62.2, 61.4, 55.6, 55.5, 39.2,

36.2, 26.3, 20.4, 19.0, 9.2; high resolution mass spectrum (ES+) m/z

451.2444 [(M + Na)⁺; calcd for C₂₆H₃₆O₅Na 451.2460].

20

epoxide (+)-20 (2.27 g, 73% yield, β:α = 14:1) as a colorless oil: [α]_D

+2.2 (c 1.7, CHCl₃); IR (neat) 2966, 2932, 2876, 1726, 1654, 1436,

1311, 1170, 1094 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.34−7.31 (m,

5H), 6.75 (d, J = 15.5 Hz, 1H), 6.00 (d, J = 16.0 Hz, 1H), 4.6 (dab, J =

11.5 Hz, 1 H), 4.52 (dab, J = 11.5 Hz, 1 H), 3.75 (s, 3H), 3.59−3.55 (m,

1H), 3.00 (dd, J = 6.5, 6.5 Hz, 1H), 1.85 (ddd, J = 14.5, 8.0, 5.5 Hz, 1H),

1.76 (ddd, J = 4.5, 6.5, 4.5 Hz, 1H), 1. 68−1.60 (m, 2H), 1.41 (s, 3H),

0.95 (dd, J = 7.5, 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 166.8,

150.4, 138.8, 128.6, 128.0, 127.9, 121.3, 78.0, 71.6, 63.8, 58.9, 51.9, 33.2,

27.0, 15.7, 9.5; high resolution mass spectrum (ES+) m/z 327.1578 [(M

+ Na)⁺; calcd for C₁₈H₂₄O₄Na 327.1572].

PMB Ether (+)-21. To a solution of compound (+)-20 (60 mg, 0.20

mmol) in CH₂Cl₂(3 mL) was added H₂O (21 μL, 6 equiv) The reaction

was cooled to −40 °C, and Me₃Al (0.98 mL, 10 equiv, 2 M in hexanes)

was added. After 30 min, the reaction was warmed to 0 °C, and the

reaction quenched with slow addition of H₂O (1 mL) followed by

addition of 1 N HCl (3 mL) to break up the emulsion. The reaction was

extracted with CH₂Cl₂(3 × 10 mL), and the combined organic layers

were dried over MgSO₄and concentrated. Flash chromatography (5%

EtOAc/hexanes to 10% EtOAc/hexanes) provided alcohol (+)-58 (53

mg, 84% yield) as a colorless oil: [α]²_D⁰+31.7 (c 1.6, CHCl₃); IR (neat)

3490, 2964, 2875, 1723, 1651, 1435, 1314, 1201, 1173, 1060 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) 7.38−7.26 (m, 5H), 7.04 (d, J = 16.1 Hz, 1H),

5.81 (d, J = 16.1 Hz, 1H), 4.60 (dab, J = 11.6 Hz, 1H), 4.52 (dab, J = 11.6

Hz, 1H), 3.73 (s, 3H), 3.70 (d, J = 8.9, 1H), 3.65−3.59 (m, 1H), 2.75 (s,

1H), 1.91−1.66 (m, 1H), 1.65−1.50 (m, 3H), 1.07 (s, 3H), 1.06 (s, 3H),

0.91 (dd, J = 7.5, 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.5,

155.9, 138.6, 128.7, 128.0, 128.0, 119.2, 78.9, 74.5, 71.6, 51.7, 41.6, 34.2,

26.1, 22.9, 22.9, 10.2; high resolution mass spectrum (ES+) m/z

343.1876 [(M + Na)⁺; calcd for C₁₉H₂₈O₄Na 343.1886].

To a solution of (+)-58 (0.906 g, 2.83 mmol) in CH₂Cl₂(9 mL) and

cyclohexane (18 mL) at rt was added p-methoxybenzyl-2,2,2-

trichloroacetimidate (3.2 g, 4.0 equiv) followed by addition of TfOH

(3 μL, 0.01 equiv). The solution turned cloudy and light brown as the

reaction progressed. After 30 min, hexane (20 mL) was added to

precipitate solids, and the suspension was ﬁltered. The ﬁltrate was

washed with sat. NaHCO₃(25 mL), which was then back-extracted with

CH₂Cl₂(3 × 25 mL). The combined organic layers were then dried over

MgSO₄and concentrated. The concentrate was diluted with 10%

EtOAc/hexanes (25 mL) to facilitate further precipitation of solids and

then ﬁltered. The ﬁltrate was then concentrated and puriﬁed by ﬂash

chromatography (3% EtOAc/hexanes to 5% EtOAc/hexanes) to

provide PMB ether (+)-21 (0.910 g, 73% yield) as a light yellow oil:

[α]²_D⁰+43.5 (c 1.6, CHCl₃); IR (neat) 2962, 2875, 2360, 2340, 1722,

Ester (+)-9. To a 0 °C solution of (+)-22 (0.233 g, 0.545 mmol) in

DMSO (6 mL) and CH₂Cl₂(7 mL) was added Et₃N (0.76 mL, 10

equiv) followed by SO₃·pyridine (0.347 g, 4 equiv). After 1.5 h,

NaHCO₃(4 mL) was added, the layers separated, and the aqueous layer

was extracted 3 × 10 mL of Et₂O. The combined organic layers were

then washed with 1 M NaHSO₄, sat. NaHCO₃, and brine (10 mL each).

The organic layer was then dried over MgSO₄and concentrated. Flash

chromatography (10% EtOAc/hexanes) provided aldehyde (+)-60

(1.43 g, 99% yield) as a colorless oil: [α]²_D⁰+115.0 (c 1.2, CHCl₃); IR

(neat) 2964, 2931, 2876, 1728, 1613, 1514, 1464, 1248, 1090, 1064,

1

1035 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 9.01 (d, J = 6.1 Hz, 1H),

7.44−7.27 (m, 5H), 7.19 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H),

4.64 (dab, J = 11.7 Hz, 1H), 4.43 (dab, J = 11.0 Hz, 1H), 4.38 (dab, J =

11.2 Hz, 1H), 4.35 (dab, J = 11.6 Hz, 1H), 3.80 (s, 3H), 3.64−3.58 (m,

1H), 3.56 (d, J = 9.8 Hz, 1H), 3.27 (dd, J = 6.1, 1.8 Hz, 1H), 3.21 (d, J =

1.8, 1H), 1.83−1.49 (m, 4H), 0.95 (s, 3H), 0.93 (dd, J = 7.5, 7.5 Hz, 3H),

0.88 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 199.1, 159.4, 139.1, 131.1,

129.2, 128.6, 127.9, 127.8, 114.0, 82.1, 76.9, 74.8, 70.0, 62.0, 56.9, 55.5,

39.6, 36.2, 26.2, 20.3, 19.1, 9.1; high resolution mass spectrum (ES+) m/

z 449.2305 [(M + Na)⁺; calcd for C₂₆H₃₄O₅Na 449.2304].

1

1613, 1513, 1248, 1173, 1064 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

7.44−7.28 (m, 5H), 7.21 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 16.0 Hz, 1H),

6.87 (d, J = 8.5 Hz, 2H), 5.83 (d, J = 16.0 Hz, 1H), 4.62 (dab, J = 11.6 Hz,

1H), 4.46 (dab, J = 10.9 Hz, 1H), 4.35 (dd, J = 2.4, 11.8 Hz, 2H), 3.80 (s,

3H), 3.75 (s, 3H), 3.66−3.56 (m, 1H), 3.50 (d, J = 9.7, 1H), 1.72−1.58

(m, 3H), 1.56−1.48 (m, 1H), 1.12 (s, 3H), 1.12 (s, 3H), 0.93 (dd, J =

7.4, 7.4 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.5, 159.2, 156.5,

139.2, 131.2, 129.2, 128.5, 127.8, 127.6, 118.6, 113.9, 83.0, 76.9, 74.9,

70.0, 55.4, 51.6, 42.7, 36.5, 26.2, 23.4, 23.4, 9.1; high resolution mass

spectrum (ES+) m/z 440.2568 [(M + )⁺; calcd for C₂₇H₃₆O₅440.2563].

Epoxy Alcohol (+)-22. A solution of (+)-21 (1.76 g, 4.0 mmol) in

CH₂Cl₂(20 mL) was cooled to −78 °C, and DIBAL-H (1.06 mL, 1.0 M

in hexanes, 2.1 equiv) was slowly added. After 5 min, the reaction was

quenched with MeOH (5 mL) followed by addition of sat. Rochelle’s

salt (10 mL). The solution was stirred for 2.5 h, and the layers were

A solution of aldehyde (+)-60 (0.445 g, 1.04 mmol) in CH₂Cl₂(5

mL) was cooled to 0 °C, and a solution of carbomethoxy

triphenylphosphonium ylide (23) in CH₂Cl₂(5 mL) was added over

1 min. The reaction was allowed to warm to rt, and after 30 min, the

solvent was evaporated. Flash chromatography (8% EtOAc/hexanes)

provided ester (+)-9 (0.453 g, 90% yield) as a light yellow oil: [α]_D²⁰

+48.7 (c 1.4, CHCl₃); IR (neat) 2962, 2876, 1725, 1612, 1513, 1463,

1

1304, 1249, 1172, 1090, 1064 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

7.41−7.26 (m, 5H), 7.17 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H),

J

dx.doi.org/10.1021/jo400260m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

6.66 (dd, J = 15.7, 7.0 Hz, 1H), 6.05 (d, J = 15.7 Hz, 1H), 4.62 (dab, J =

11.6 Hz, 1H), 4.43 (dab, J = 10.9 Hz, 1H), 4.37 (dab, J = 11.2 Hz, 1H),

4.34 (dab, J = 11.8 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.63−3.56 (m,

1H), 3.53 (d, J = 9.2 Hz, 1H), 3.35 (dd, J = 6.9, 1.7 Hz, 1H), 2.88 (d, J =

1.9 Hz, 1H), 1.81−1.50 (m, 4H), 0.94 (s, 3H), 0.93 (dd, J = 7.4, 7.4 Hz,

3H), 0.86 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 166.4, 159.3, 145.6,

139.2, 131.3, 129.0, 128.6, 128.6, 127.9, 127.7, 123.2, 114.0, 82.1, 76.9,

74.6, 70.0, 67.0, 55.5, 53.8, 51.9, 39.9, 36.1, 26.3, 20.7, 18.6, 9.2; high

resolution mass spectrum (ES+) m/z 505.2553 [(M + Na)⁺; calcd for

C₂₉H₃₈O₆Na 505.2566].

11.4 Hz, 1H), 4.50 (dab, J = 10.9 Hz, 1H), 4.35 (dab, J = 10.8 Hz, 1H),

4.34 (dab, J = 11.2 Hz, 1H), 4.03−3.91 (m, 2H), 3.80 (s, 3H), 3.64−3.59

(m, 1H), 3.58 (dd, J = 9.7, 1.3 Hz, 1H), 3.55 (dd, J = 5.3, 5.3 Hz, 1H),

2.41 (ddd, J = 14.5, 5.4 Hz, 1H), 2.19 (ddd, J = 14.0, 6.7 Hz, 1H), 1.75−

1.64 (m, 1H), 1.64−1.49 (m, 3H), 1.47 (dd, J = 6.0, 6.0 Hz, 1H), 0.98 (s,

3H), 0.92 (dd, J = 7.5, 7.5 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 3H), 0.04 (s,

6H); ¹³C NMR (125 MHz, CDCl₃) δ 159.2, 139.1, 131.8, 131.4, 130.7,

129.0, 128.6, 128.1, 127.7, 113.9, 80.9, 77.3, 75.0, 70.5, 63.8, 55.5, 45.0,

36.4, 36.0, 26.3, 26.3, 21.0, 19.9, 18.6, 9.2, −3.1, −3.9; high resolution

mass spectrum (ES+) m/z 593.3651 [(M + Na)⁺; calcd for

C₃₄H₅₄O₅SiNa 593.3639].

TBS Ether (+)-24. To freshly distilled dioxane (2 mL) was added

Pd₂(dba)₃·CHCl₃(46 mg, 0.05 equiv) and n-Bu₃P (13 μL, 0.06 equiv).

Next, a solution of HCO₂H (0.20 mL, 6.0 equiv) and Et₃N (0.25 mL, 2

equiv) in dioxane (1 mL) was added. This mixture was stirred at rt for 10

min, and then a solution of epoxide (+)-9 (0.452 g, 0.937 mmol) in

dioxane (1.5 mL) was added via cannula. The ﬂask and cannula were

rinsed with dioxane (2 × 1 mL) into the reaction ﬂask. After 4.5 h, the

reaction mixture was ﬁltered through a 1 cm plug of silica gel, and the

silica gel washed with CH₂Cl₂(20 mL). The ﬁltrate was concentrated

and subjected to ﬂash chromatography (5% EtOAc/hexanes to 10%

EtOAc/hexanes to 15% EtOAc/hexanes) to provide alcohol (+)-61

(0.421 g, 93% yield) as a colorless oil: [α]²_D⁰+95.5 (c 0.7, CHCl₃); IR

(neat) 3464, 2963, 2875, 1722, 1613, 1514, 1249, 1173, 1063, 1036

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.40−7.26 (m, 5H), 7.13 (d, J =

8.2 Hz, 2H), 7.08 (ddd, J = 14.8, 7.2, 7.2 Hz, 1H), 6.83 (d, J = 8.3 Hz,

2H), 5.90 (d, J = 15.6 Hz, 1H), 4.64 (dab, J = 11.7 Hz, 1H), 4.44 (dab, J =

10.7 Hz, 1H) 4.34 (dab, J = 12.0 Hz, 1H), 4.34 (dab, J = 12.0 Hz, 1H),

4.32 (dab, J = 11.1 Hz, 1H), 4.16 (s, 1H), 3.79 (s, 3H), 3.71 (s, 3H),

3.59−3.56 (m, 1H), 3.54 (d, J = 9.2 Hz, 1H), 2.25 (m, 2H), 1.91−1.67

(m, 3H), 1.62 (ddd, J = 14.1, 7.1, 7.1 Hz, 1H), 1.08 (s, 3H), 0.93 (dd, J =

7.4, 7.4 Hz, 3H), 0.83 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.1,

159.5, 148.0, 139.1, 130.4, 129.2, 128.6, 128.0, 127.8, 122.6, 114.1, 86.7,

77.1, 75.3, 75.0, 70.1, 55.5, 51.5, 41.5, 35.8, 35.1, 26.3, 23.3, 20.4, 9.2;

high resolution mass spectrum (ES+) m/z 485.2888 [(M + H)⁺; calcd

for C₂₉H₄₁O₆485.2903].

To a 0 °C solution of alcohol (+)-61 (0.789 g, 1.63 mmol) in CH₂Cl₂

(16.3 mL) was added 2,6-lutidine (0.38 mL, 2.0 equiv) followed by

dropwise addition of TBSOTf (0.45 mL, 1.2 equiv). After 20 min, sat.

NaHCO₃(10 mL) was added, and the layers separated. The aqueous

layer was extracted CH₂Cl₂(3 × 15 mL), and the combined organic

layers were dried over MgSO₄and concentrated. Flash chromatography

(5% EtOAc/hexanes) provided TBS ester (+)-24 (0.965 g, 99% yield)

as a colorless oil: [α]²_D⁰+42.1 (c 0.9, CHCl₃); IR (neat) 2956, 2931,

2881, 2855, 1725, 1513, 1463, 1249, 1170, 1073 cm⁻¹; ¹H NMR (500

MHz, CDCl₃) δ 7.37−7.26 (m, 5H), 7.20 (d, J = 8.5 Hz, 2H), 7.06 (ddd,

J = 15.7, 8.3, 6.4 Hz, 1H), 6.86 (d, J = 8.5 Hz, 2H), 5.76 (d, J = 15.7 Hz,

1H), 4.64 (dab, J = 11.5 Hz, 1H), 4.47 (dab, J = 10.9 Hz, 1H), 4.33 (dab,

J = 10.8 Hz, 1H), 4.32 (dab, J = 11.7 Hz, 1H), 3.80 (s, 3H), 3.73 (s, 3H),

3.65 (dd, J = 6.4, 4.0 Hz, 1H), 3.60−3.55 (m, J = 9.9, 5.5 Hz, 1H), 3.52

(dd, J = 6.5, 5.0 Hz, 1H), 2.51 (ddd, J = 14.9, 4.2, 4.2 Hz, 1H), 2.36 (ddd,

J = 15.0, 7.5, 7.5 Hz, 1H), 1.74−1.64 (m, 1H), 1.65−1.58 (m, 1H), 1.56

(dd, J = 5.9, 5.9 Hz, 2H), 0.95 (s, 3H), 0.92 (dd, J = 7.5, 7.5 Hz, 3H), 0.90

(s, 9H), 0.89 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 167.1, 159.2, 148.6, 139.2, 131.7, 129.0, 128.6, 127.8, 127.7,

122.2, 113.9, 81.3, 77.3, 76.6, 75.0, 70.3, 55.5, 51.5, 44.7, 36.2, 36.1, 26.3,

26.2, 21.0, 20.1, 18.6, 9.2, −3.2, −3.8; high resolution mass spectrum (ES

+) m/z 621.3605 [(M + Na)⁺; calcd for C₃₅H₅₄O₆SiNa 621.3588].

Epoxide (+)-25. A solution of (+)-24 (1.43 g, 2.38 mmol) in CH₂Cl₂

(12 mL) was cooled to −78 °C, and DIBAL-H (1.06 mL, 1.0 M in

hexanes, 2.1 equiv) was added slowly over 5 min. After 2 min, the

reaction was quenched with methanol (1 mL) followed by addition of

sat. Rochelle’s salt (10 mL). The solution was stirred for 2 h, and the

layers were separated. The aqueous layer was extracted with CH₂Cl₂(3

× 25 mL), and the combined organic layers were dried over MgSO₄and

then concentrated. Flash chromatography (5% EtOAc/hexanes)

provided allylic alcohol (+)-62 (1.32 g, 97%) as a colorless oil: [α]_D²⁰

+47.7 (c 0.7, CHCl₃); IR (neat) 3444, 2958, 2930, 2880, 2855, 1613,

1514, 1463, 1249, 1070 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.41−7.27

(m, 5H), 7.21 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.74 (ddd, J =

15.2, 7.2 Hz, 1H), 5.55 (ddd, J = 15.4, 5.8, 5.8 Hz, 1H), 4.64 (dab, J =

To freshly activated 3 Å molecular sieves (0.4 g) in CH₂Cl₂(4.6 mL)

was added (−)-DIPT (58 μL, 0.12 equiv). The solution was cooled to

−20 °C, and Ti(Oi-Pr)₄(68 μL, 0.1 equiv) was added followed by t-

BuOOH (1.26 mL, 5.5 M in decane, 3.0 equiv). The reaction was stirred

for 30 min, and then allylic alcohol (+)-62 (1.32 g, 2.31 mmol) dissolved

in CH₂Cl₂(2 mL) was added via cannula. The ﬂask and cannula were

rinsed with CH₂Cl₂(2 × 1.5 mL) into the reaction ﬂask. After 4 h, 10%

aq. citric acid (10 mL) was added, and the reaction warmed to rt. After 2

h, the layers were separated, and the aqueous layer extracted with

CH₂Cl₂(3 × 25 mL). The combined organic layers were dried over

MgSO₄and concentrated. Flash chromatography (10% EtOAc/hexanes

to 15% EtOAc/hexanes) provided epoxide (+)-25 (1.24 g, 92% yield, dr

> 20:1) as a colorless oil: [α]_D²⁰+72.4 (c 1.9, CHCl₃); IR (neat) 3444,

2957, 2930, 2881, 2856, 1613, 1514, 1463, 1249, 1071 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ 7.39−7.27 (m, 5H), 7.22 (d, J = 8.5 Hz, 2H), 6.86

(d, J = 8.6 Hz, 2H), 4.61 (dab, J = 11.3 Hz, 1H), 4.50 (dab, J = 10.9 Hz,

1H), 4.37 (dab, J = 10.8 Hz, 1H), 4.31 (dab, J = 11.3 Hz, 1H), 3.80 (s,

3H), 3.78−3.71 (m, 2H), 3.62−3.51 (m, 2H), 3.49 (dd, J = 9.3, 2.0 Hz,

1H), 3.10 (ddd, J = 6.8, 4.7, 2.1 Hz, 1H), 2.70 (dd, J = 4.3, 2.6 Hz, 1H),

1.80−1.64 (m, 3H), 1.64−1.50 (m, 3H), 0.98 (s, 3H), 0.92 (s, 12H),

0.92 (dd, J = 7.4, 7.4 Hz, 3H), 0.11 (s, 3H), 0.10 (s, 3H); ¹³C NMR (125

MHz, CDCl₃) δ 159.2, 139.3, 131.7, 129.0, 128.5, 127.9, 127.6, 113.9,

81.4, 77.3, 75.1, 75.0, 70.0, 61.7, 59.9, 55.5, 53.7, 44.2, 35.9, 35.1, 26.4,

26.2, 20.9, 20.0, 18.6, 9.2, −3.5, −3.6; high resolution mass spectrum (ES

+) m/z 609.3596 [(M + Na)⁺; calcd for C₃₄H₅₄O₆SiNa 609.3588].

Alcohol (+)-26. Epoxy alcohol (+)-25 was dissolved in CH₃CN (12

mL), and then TEMPO (15 mg, 0.08 equiv) was added followed by pH

7 buﬀer (12 mL). Next, NaClO₂(0.42 g, 2.5 equiv) was added in one

portion followed by dropwise addition of NaOCl (0.32 mL, 5 wt %

solution, 0.2 equiv). After 1.5 h, anhydrous Na₂SO₃(0.49 g, 3.2 equiv)

was added, and the reaction stirred for 30 min, upon which the solution

turned from orange to colorless. The reaction was acidiﬁed to pH 4 with

10% aq. citric acid solution and then extracted with EtOAc (3 × 25 mL).

The combined organic layers were dried over MgSO₄and concentrated.

The unpuriﬁed acid was then dissolved in Et₂O (24 mL) and cooled

to 0 °C. A solution of CH₂N₂in Et₂O was then added dropwise until gas

evolution ceased, and the reaction turned light yellow. Argon was

bubbled through the reaction mixture for 15 min to remove any excess

CH₂N₂, and then the reaction was concentrated. Flash chromatography

(10% EtOAc/hexanes) provided methyl ester (+)-63 (0.557 g, 76%

yield, 2 steps) as a colorless oil: [α]²_D⁰+86.8 (c 1.0, CHCl₃); IR (neat)

2957, 2931, 2882, 2857, 1754, 1513, 1458, 1249, 1065 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ 7.41−7.27 (m, 5H), 7.21 (d, J = 8.6 Hz, 2H), 6.86

(d, J = 8.7 Hz, 2H), 4.62 (dab, J = 11.5 Hz, 1H), 4.50 (dab, J = 10.9 Hz,

1H), 4.36 (dab, J = 10.9 Hz, 1H), 4.30 (dab, J = 11.4 Hz, 1H), 3.80 (s,

3H), 3.75 (s, 3H), 3.75−3.70 (m, 1H), 3.60−3.53 (m, 1H), 3.49−3.42

(m, 1H), 3.31 (ddd, J = 6.5, 4.5, 1.8 Hz, 1H), 3.04 (d, J = 1.8 Hz, 1H),

1.80 (ddd, J = 14.5, 7.7, 4.5 Hz, 1H), 1.71−1.64 (m, 2H), 1.64−1.56 (m,

1H), 1.54 (dd, J = 7.6, 4.5 Hz, 2H), 0.96 (s, 3H), 0.93−0.90 (m, 15H),

0.12 (s, 3H), 0.09 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.9, 159.2,

139.3, 131.6, 129.0, 128.6, 127.8, 127.7, 113.9, 81.4, 77.1, 75.1, 74.9,

70.0, 56.6, 55.5, 54.7, 52.5, 44.2, 35.9, 34.8, 26.4, 26.1, 21.0, 20.0, 18.6,

9.1, −3.6, −3.6; high resolution mass spectrum (ES+) m/z 637.3521

[(M + Na)⁺; calcd for C₃₅H₅₄O₇SiNa 637.3537].

A solution of (+)-63 (1.32 g, 2.14 mmol) in CH₂Cl₂(22 mL) and pH

7 buﬀer (5.4 mL) was cooled to 0 °C, and DDQ (0.542 g, 1.1 equiv) was

added in three portions over 1 min. After 45 min, the reaction was

diluted with CH₂Cl₂(20 mL) and ﬁltered through Celite. The Celite

was then washed with sat. NaHCO₃(10 mL). The layers were separated,

K

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and the aqueous layer extracted with CH₂Cl₂(3 × 20 mL). The

combined organic layers were then dried with MgSO₄and concentrated.

Flash chromatography (5% EtOAc/hexanes until the anisaldehyde

eluted then 10% EtOAc/hexanes) provided alcohol (+)-26 (0.998g,

94% yield) as a light yellow oil: [α]²_D⁰+54.3 (c 0.7, CHCl₃); IR (neat)

3494, 2957, 2930, 2880, 2855, 1755, 1452, 1254, 1204, 1058 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ 7.42−7.23 (m, 5H), 4.63 (dab, J = 11.6 Hz,

1H), 4.53 (dab, J = 11.6 Hz, 1H) 3.91 (dd, J = 8.8, 3.2 Hz, 1H), 3.84 (s,

1H), 3.82−3.76 (m, 1H), 3.77 (s, 3H), 3.69 (ddd, J = 11.4, 5.9, 5.9 Hz,

1H), 3.32 (ddd, J = 7.9, 3.3, 1.9 Hz, 1H), 3.23 (d, J = 1.8 Hz, 1H), 1.98

(ddd, J = 14.8, 8.2, 3.4 Hz, 1H), 1.69−1.52 (m, 3H), 1.50−1.45 (m, 2H),

0.95 (s, 3H), 0.94−0.91 (m, 12H), 0.72 (s, 3H), 0.16 (s, 3H), 0.15 (s,

3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.6, 139.5, 128.5, 127.9, 127.6,

79.5, 78.2, 72.2, 71.4, 56.6 54.4, 52.7, 40.9, 36.1, 35.2, 27.5, 26.3, 22.5,

20.0, 18.5, 9.9, −3.7, −4.1; high resolution mass spectrum (ES+) m/z

495.3125 [(M + H)⁺; calcd for C₂₇H₄₇O₆Si 495.3142].

Alcohol (+)-27. To a solution of (+)-26 (0.998 g, 2.02 mmol) in

CH₂Cl₂(40 mL) was added camphorsulfonic acid (94 mg, 0.2 equiv).

After stirring for 5 h at rt, sat. NaHCO₃(20 mL) was added, and the

reaction mixture stirred for 10 min. The layers were separated, and the

aqueous layer extracted with CH₂Cl₂(4 × 15 mL). The combined

organic layers were then dried over MgSO₄and concentrated. Flash

chromatography (5% EtOAc/hexanes) provided alcohol (+)-27

(0.917g, 92%) as a colorless oil: [α]²_D⁰+38.1 (c 1.6, CHCl₃); IR (neat)

3461, 2956, 2930, 2857, 1741, 1471, 1437, 1360, 1256, 1080 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ 7.44−7.17 (m, 5H), 4.54 (dd, J = 41.3, 11.5

Hz, 2H), 4.23 (dd, J = 5.8, 4.0 Hz, 1H), 4.07 (dd, J = 9.9, 3.5 Hz, 1H),

3.78 (s, 3H), 3.80−3.75 (m, 1H), 3.63 (dd, J = 3.8, 3.8 Hz, 1H), 3.56−

3.48 (m, 1H), 2.87 (d, J = 6.2 Hz, 1H), 2.31 (dd, J = 13.0, 13.0 Hz, 1H),

2.06 (ddd, J = 13.4, 10.0, 3.1 Hz, 1H), 1.71−1.48 (m, 3H), 1.36 (ddd, J =

13.6, 3.9, 3.9 Hz, 1H), 1.01 (s, 3H), 0.92 (dd, J = 7.5, 7.5 Hz, 3H), 0.90

(s, 9H), 0.86 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 173.2, 139.5, 128.5, 128.4, 128.0, 127.5, 77.9, 73.8, 73.7, 71.6,

67.6, 52.6, 37.3, 33.0, 30.1, 27.2, 26.5, 26.0, 21.5, 18.2, 9.6, −4.4, −4.9;

high resolution mass spectrum (ES+) m/z 517.2970 [(M + Na)⁺; calcd

for C₂₇H₄₆O₆SiNa 517.2962].

Methyl Ether (+)-28. A solution of (+)-27 (0.236g, 0.478 mmol) in

THF (5 mL) was cooled to 0 °C, and NaH (29 mg, 60% in mineral oil,

1.5 equiv) added in one portion. After 20 min, Me₂SO₄(59 μL, 1.3

equiv) was added dropwise, and the reaction allowed to warm to rt. After

1.5 h, the reaction was quenched with sat. NaHCO₃(5 mL). The layers

were separated, and the aqueous layer extracted with CH₂Cl₂(5 × 15

mL). The combined organic layers were then dried over MgSO₄and

concentrated. Flash chromatography (3% EtOAc/hexanes to 5%

EtOAc/hexanes) provided methyl ether (+)-28 (0.229g, 94% yield) as

a colorless oil: [α]²_D⁰+20.0 (c 2.8, CHCl₃); IR (neat) 2956, 2931, 2857,

1751, 1462, 1359, 1256, 1195, 1126, 1083, 1006 cm⁻¹; ¹H NMR (500

MHz, CDCl₃) δ 7.44−7.14 (m, 5H), 4.57 (dab, J = 11.5 Hz, 1H), 4.51

(dab, J = 11.4 Hz, 1H), 4.08 (ddd, J = 7.1, 4.2, 4.2 Hz, 1H), 3.89 (d, J =

6.4 Hz, 1H), 3.74 (s, 3H), 3.70 (dd, J = 11.3, 1.5 Hz, 1H), 3.59 (dd, J =

6.5, 3.4 Hz, 1H), 3.50−3.44 (m, 1H), 3.39 (s, 3H), 2.08 (dd, J = 12.7,

12.7 Hz, 1H), 1.98 (ddd, J = 13.7, 7.6, 3.5 Hz, 1H), 1.70−1.48 (m, 4H),

1.00 (s, 3H), 0.92 (dd, J = 7.6, 7.6 Hz, 3H), 0.90 (s, 9H), 0.85 (s, 3H),

0.05 (s, 3H), 0.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.8, 139.8,

128.4, 127.8, 127.4, 83.2, 78.0, 77.9, 73.5, 71.6, 68.4, 58.8, 52.1, 37.9,

33.7, 30.7, 27.4, 26.0, 25.9, 19.2, 18.2, 9.6, −4.3, −4.9; high resolution

mass spectrum (ES+) m/z 531.3139 [(M + Na)⁺; calcd for

C₂₈H₄₈O₆SiNa 531.3118].

Tetrahydropyran (+)-6. To a solution of (+)-28 (0.229 g, 0.450

mmol) in EtOAc (4.5 mL) was added 10% Pd/C (0.025 g). The reaction

ﬂask was purged with H₂, and then a balloon of H₂was attached to the

ﬂask. After 5 h at rt, the reaction mixture was ﬁltered through a pad of

Celite, and the Celite rinsed with CH₂Cl₂(10 mL). The reaction was

concentrated, and then ﬂash chromatography (10% EtOAc/hexanes)

provided alcohol (+)-64 (0.182 g, 97%) as a colorless oil: [α]²_D⁰+12.7 (c

3.6, CHCl₃); IR (neat) 3557, 2955, 2930, 2857, 1730, 1463, 1285, 1254,

1127, 1082 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 4.08 (d, J = 9.0 Hz,

1H), 4.04−4.00 (m, 1H), 3.81 (s, 3H), 3.59−3.53 (m, 2H), 3.53−3.46

(m, 1H), 3.41 (s, 3H), 2.92 (d, J = 4.1 Hz, 1H), 1.93 (ddd, J = 13.8, 4.2,

2.8 Hz, 1H), 1.74 (ddd, J = 13.8, 10.4, 5.7 Hz, 1H), 1.60 (dd, J = 12.3,

12.3 Hz, 1H), 1.53−1.34 (m, 3H), 0.94 (dd, J = 7.4, 7.4 Hz, 3H), 0.89 (s,

12H), 0.83 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 173.1, 81.0, 76.1, 72.6, 72.2, 68.8, 58.8, 52.6, 39.0, 36.5, 30.4,

30.2, 26.0, 23.8, 18.2, 14.2, 10.6, −4.1, −4.8; high resolution mass

spectrum (ES+) m/z 441.2642 [(M + Na)⁺; calcd for C₂₁H₄₂O₆SiNa

441.2649].

A solution of alcohol (+)-64 (0.187g, 0.446 mmol) in CH₂Cl₂(4.5

mL) was cooled to 0 °C, and NaHCO₃(56 mg, 1.5 equiv) was added

followed by Dess−Martin periodinane (0.568 g, 3 equiv). After 1 h at 0

°C, H₂O, sat. NaHCO₃, and CH₂Cl₂(5 mL each) were added. The

solution was stirred until the organic layer went clear (ca. 30 min). The

layers were separated, and the aqueous layer extracted with CH₂Cl₂(3 ×

10 mL). The combined organic layers were then dried over MgSO₄and

concentrated. Flash chromatography (10% EtOAc/hexanes) provided

tetrahydropyran (+)-6 (0.181g, 97% yield) as a colorless oil: [α]²_D⁰+16.5

(c 1.7, CHCl₃); IR (neat) 2954, 2934, 2886, 2858, 1754, 1722, 17.112,

1462, 1361, 1255, 1119, 1073 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 4.10

(dd, J = 10.6, 2.5 Hz, 1H), 4.04 (ddd, J = 11.9, 4.5, 2.3 Hz, 1H), 3.80 (d, J

= 4.5 Hz, 1H), 3.70 (s, 3H), 3.53 (dd, J = 2.7, 2.7 Hz 1H), 3.40 (s, 3H),

2.60−2.38 (m, 3H), 2.23 (dd, J = 14.5, 2.5 Hz, 1H), 1.96 (ddd, J = 14.1,

12.0, 2.4 Hz, 1H), 1.40 (ddd, J = 13.8, 3.1, 2.5 Hz, 1H), 1.04 (dd, J = 7.3,

7.3 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 3H), 0.80 (s, 3H), 0.03 (s, 3H), 0.01

(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 210.4, 171.7, 82.5, 77.4, 73.1,

69.8, 58.8, 52.2, 42.6, 38.1, 37.2, 30.3, 26.0, 25.1, 18.2, 17.9, 7.8, −4.2,

−4.8; high resolution mass spectrum (ES+) m/z 439.2491 [(M + Na)⁺;

calcd for C₂₁H₄₀O₆SiNa 439.2492].

β-Hydroxy Ketone (+)-29. A solution of ketone (+)-6 (0.140 g,

0.336 mmol) in CH₂Cl₂(3.4 mL) was cooled to −78 °C, and Cl₂BPh

(52 μL, 1.2 equiv) was added. After stirring for 20 min, i-Pr₂NEt (88 μL,

1.5 equiv) was added dropwise. The reaction was stirred for 1 h at −78

°C, warmed to 0 °C over 10 min, and then stirred for 1 h at 0 °C. After

cooling back to −78 °C, aldehyde 5 (0.237g, 1.45 equiv) was dissolved

in CH₂Cl₂(1.5 mL) and added to the boron enolate dropwise over 15

min. After 1 h at −78 °C, the reaction was quenched with a 1:1 mixture

of MeOH/pH 7 buﬀer (6 mL). After warming to 0 °C, the reaction was

neutralized to pH 7 with pH 8 buﬀer and stirred for 1 h at 0 °C. The

layers were separated, and the aqueous layer extracted with CH₂Cl₂(3 ×

15 mL). The combined organic layers were then dried over MgSO₄and

concentrated. Flash chromatography (15% EtOAc/hexanes) provided

β-hydroxy ketone (+)-29 (0.273 g, 90% yield, single diastereomer) as a

colorless oil: [α]²_D⁰+30.0 (c 0.9, CHCl₃); IR (neat) 3467, 2952, 2896,

1731, 1593, 1463, 1253, 1064 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 6.88

(s, 1H), 5.21 (s, 2H), 5.15 (d, J = 2.3 Hz, 2H), 4.09 (dd, J = 11.1, 5.7 Hz,

1H), 4.07−4.00 (m, 2H), 3.94 (d, J = 6.1 Hz, 1H), 3.87 (s, 3H), 3.78−

3.70 (m, 4H), 3.72 (s, 3H), 3.64 (dd, J = 7.8, 3.8 Hz, 1H), 3.43 (d, J = 5.6

Hz, 1H), 3.40 (s, 3H), 3.06 (dd, J = 16.4, 9.4 Hz, 1H), 2.84 (dd, J = 14.2,

3.2 Hz, 1H), 2.75−2.63 (m, 1H), 2.61−2.50 (m, 2H), 2.16 (s, 3H), 1.95

(ddd, J = 13.8, 5.8, 3.9 Hz, 1H), 1.57 (ddd, J = 13.3, 7.8, 4.9 Hz, 1H), 1.19

(d, J = 7.1 Hz, 3H), 0.95 (s, 3H), 0.98−0.92 (m, 4H), 0.90 (s, 9H), 0.84

(s, 3H), 0.04 (s, 6H), 0.01 (s, 9H), 0.00 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) δ 212.5, 171.6, 170.7, 157.8, 153.7, 136.6, 120.3, 119.1, 101.1,

93.9, 93.3, 82.4, 76.7, 73.1, 71.6, 70.1, 66.5, 66.5, 58.8, 53.2, 52.7, 52.2,

42.5, 38.1, 35.9, 30.1, 26.0, 24.9, 18.3, 18.2, 17.6, 11.8, 11.4, −1.2, −4.3,

−4.8; high resolution mass spectrum (ES+) m/z 923.4782 [(M + Na)⁺;

calcd for C₄₄H₈₀O₁₃Si₃Na 923.4805].

Acid (+)-30. A solution (+)-29 (0.116 g, 0.129 mmol) in THF (1.4

mL) and MeOH (0.46 mL) was cooled to −78 °C, and Et₂BOMe (0.167

mL, 1 M in THF, 1.3 equiv) was added dropwise. After 25 min, NaBH₄

(10 mg, 2.0 equiv) was added, and the reaction was strirred at −78 °C.

After 1 h, the reaction was warmed to 0 °C over 10 min and then stirred

for 30 min. EtOAc (2 mL) was added followed by H₂O (2 mL) and a 1:1

solution of MeOH/30% aq. H₂O₂(5 mL). After 1 h, the reaction was

extracted with EtOAc (3 × 10 mL), and the combined organic layers

were treated with solid Na₂S₂O₃to destroy any remaining peroxide. The

organic layer was then ﬁltered and washed with sat. Na₂S₂O₃, dried over

MgSO₄, and concentrated. Flash chromatography (15% EtOAc/

hexanes to 25% EtOAc/hexanes) provided diol (+)-65 (0.109 g, 95%

yield, dr > 20:1) as a colorless oil: [α]²_D⁰+10.3 (c 1.0, CHCl₃); IR (neat)

3500, 2953, 2896, 2857, 1734, 1593, 1253, 1157, 1115, 1065 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ 6.87 (s, 1H), 5.21 (s, 2H), 5.16 (s, 2H),

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4.16−4.10 (m, 1H), 4.02 (dd, J = 7.5, 4.9 Hz, 1H), 3.97 (d, J = 7.9 Hz,

1H), 3.88 (s, 3H), 3.84 (dd, J = 12.9, 7.1 Hz, 1H), 3.78 (s, 3H), 3.76−

3.70 (m, 4H), 3.65 (s, 1H), 3.56−3.50 (m, 2H), 3.39 (s, 3H), 2.85−2.80

(m, 2H), 2.20 (s, 3H), 1.93 (ddd, J = 13.8, 4.0, 4.0 Hz, 1H), 1.83 (ddd, J

= 14.2, 10.3, Hz, 1H), 1.72−1.63 (m, 1H), 1.51 (d, J = 7.0 Hz, 1H), 1.45

(d, J = 14.7 Hz, 1H), 0.98 (d, J = 6.9, 3H), 0.96−0.92 (m, 4H), 0.90 (s,

9H), 0.88 (s, 3H), 0.85 (s, 3H), 0.04 (s, 3H), 0.04 (s, 3H), 0.01 (s, 9H),

0.00 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 171.3, 169.9, 157.2, 153.1,

136.9, 120.2, 119.2, 100.6, 93.6, 93.1, 81.7, 80.9, 76.2, 75.5, 72.1, 71.4,

66.2, 66.2, 58.5, 52.2, 52.2, 41.9, 38.9, 35.8, 33.4, 29.8, 25.7, 24.0, 18.0,

17.9, 15.1, 11.7, 5.8, −1.5, −4.4, −5.0; high resolution mass spectrum

(ES+) m/z 925.5000 [(M + Na)⁺; calcd for C₄₄H₈₂O₁₃Si₃Na 925.4961].

A solution of diol (+)-65 (20.6 mg, 0.023 mmol) was dissolved in

MeOH (1.1 mL) and cooled to 0 °C. Next, H₂O (8 μL, 20 equiv) was

added followed by LiOH (11 mg, 20 equiv). The cold bath was removed,

and the reaction allowed to warm to rt. After 28 h, because of bis-acid

formation, the reaction was quenched by diluting with EtOAc and

acidiﬁed to pH 5 with 5% aq. AcOH. Brine (2 mL) was added, and the

reaction extracted with EtOAc (5 × 3 mL). The combined organic layers

were then dried over MgSO₄and concentrated. Flash chromatography

(0.1% AcOH in 30% EtOAc/hexanes to 0.2% AcOH in 60% EtOAc/

hexanes) provided acid (+)-30 (17 mg, 87% yield) as a colorless oil:

[α]²_D⁰+31.4 (c 1.1, CHCl₃); IR (neat) 3467, 2953, 2898, 2858, 1720,

1592, 1250, 1107, 1065 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 6.95 (s,

1H), 5.30 (dd, J = 20.0, 7.0 Hz, 2H), 5.27 (s, 2H), 4.33 (ddd, J = 12.1,

5.8, 2.5 Hz, 1H), 4.23 (dd, J = 10.9, 6.6 Hz, 1H), 4.15 (d, J = 7.3 Hz, 1H),

3.87−3.79 (m, 3H), 3.78−3.72 (m, 2H), 3.64−3.57 (m, 2H), 3.45 (s,

3H), 3.03 (dd, J = 16.5, 2.4 Hz, 1H), 2.91 (dd, J = 16.4, 12.2 Hz, 1H),

2.24−2.07 (m, 1H), 2.12 (s, 3H), 2.01 (dd, J = 10.6, 7.0 Hz, 1H), 1.97−

1.92 (m, 1H), 1.66 (ddd, J = 13.7, 6.8, 4.7 Hz, 1H), 1.54 (d, J = 15.0 Hz,

1H), 1.08 (d, J = 7.0 Hz, 3H), 0.97 (s, 3H), 0.99−0.94 (m, 4H), 0.91 (s,

9H), 0.88 (s, 3H), 0.06 (s, 6H), 0.01 (s, 9H), 0.00 (s, 9H); ¹³C NMR

(125 MHz, CDCl₃) δ 172.3, 164.1, 160.1, 159.2, 141.9, 117.45, 109.0,

102.1, 94.4, 93.1, 82.2, 81.9, 79.0, 72.7, 71.9, 69.8, 66.8, 66.8, 58.7, 41.7,

38.7, 33.0, 30.6, 29.5, 26.0, 25.0, 18.3, 18.3, 18.2, 11.4, 9.7, 9.7, −1.2,

−1.2, −4.2, −4.8; high resolution mass spectrum (ES+) m/z 879.4569

[(M + Na)⁺; calcd for C₄₂H₇₆O₁₂Si₃Na 879.4543].

Silyl Ether (+)-4. A solution of (+)-30 (54 mg, 0.063 mmol) in

acetone (3.2 mL) was cooled to 0 °C, and i-Pr₂NEt (24 μL, 2.2 equiv)

was added followed by dropwise addition of isobutyl chloroformate (20

μL, 2.4 equiv). After 45 min at 0 °C, NaN₃(21 mg, 5 equiv) was

dissolved in H₂O (0.4 mL) and added to the reaction over 2 min. After

20 min, cold H₂O (2 mL) was added, and the reaction extracted with

cold EtOAc (3 × 5 mL). The combined organic layers were dried

thoroughly over MgSO₄and concentrated. The residue was azeotroped

with benzene (3 × 5 mL) and placed on the vacuum pump for 30 min.

The unpuriﬁed acyl azide was dissolved in toluene (3.2 mL), the reaction

ﬂask ﬁtted with a reﬂux condenser, and then heated to 80 °C. After 45

min, 2-trimethylsilyl ethanol (0.181 mL, 20 equiv) was added through

the top of the reﬂux condenser. After 2 h, the reaction was cooled to rt,

and the solvent evaporated. Flash chromatography (10% EtOAc/

hexanes to 25% EtOAc/hexanes) provided N,O-aminal (+)-43 (45 mg,

74% yield) as a colorless oil: [α]²_D⁰+8.4 (c 0.5, CHCl₃); IR (neat) 3501,

3315, 2953, 2901, 2857, 1719, 1595, 1249, 1108, 1064 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ 6.94 (s, 1H), 5.37 (d, J = 10.1 Hz, 1H), 5.31 (dab, J

= 7.0 Hz, 1H), 5.27 (dab, J = 6.7 Hz, 1H), 5.26 (s, 1H), 4.89 (dd, J = 10.0,

2.6 Hz, 1H), 4.31 (ddd, J = 11.6, 6.9. 2.4 Hz, 1H), 4.24−4.08 (m, 2H),

3.97 (d, J = 9.4 Hz, 1H), 3.88−3.72 (m, 4H), 3.65 (s, 1H), 3.62 (d, J =

10.4 Hz, 1H), 3.56 (dd, J = 4.9, 3.2 Hz, 1H), 3.36 (s, 3H), 3.10 (dd, J =

16.4, 2.1 Hz, 1H), 2.82 (dd, J = 16.4, 11.9 Hz, 1H), 2.45−2.28 (m, 1H),

2.12 (s, 3H), 1.91−1.80 (m, J = 12.5, 8.0 Hz, 2H), 1.53−1.37 (m, 2H),

1.11 (d, J = 6.9 Hz, 3H), 1.00 (s, 3H), 0.98−0.93 (m, 6H), 0.90 (s, 9H),

0.88 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.02 (s, 9H), 0.00 (s, 9H), 0.00

(s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 163.5, 159.9, 159.1, 157.2,

141.9, 117.4, 109.4, 102.2, 94.4, 93.1, 83.8, 83.6, 79.4, 77.4, 73.0, 72.7,

68.0, 66.8, 66.7, 63.7, 55.8, 43.4, 38.1, 32.9, 31.1, 29.7, 26.1, 26.0, 18.4,

18.3, 18.2, 17.8, 11.4, 10.2, −1.1, −1.2, −1.3, −4.3, −4.8; high resolution

mass spectrum (ES+) m/z 994.5354 [(M + Na)⁺; calcd for

C₄₇H₈₉NO₁₂Si₄Na 994.5360].

A solution of N,O-aminal (+)-43 (19.6 mg, 0.020 mmol) in CH₂Cl₂

(0.2 mL) was cooled to 0 °C, and 2,6-lutidine (9.5 μL, 4.0 equiv) was

added followed by dropwise addition of TBSOTf (10 μL, 2.1 equiv).

After 45 min, CH₂Cl₂(1 mL) and sat. NaHCO₃(2 mL) added, and the

reaction allowed to warm to rt. The layers were separated, and the

aqueous layer extracted with CH₂Cl₂(3 × 5 mL). Preparative TLC

(25% EtOAc/hexanes, 500 μm plate) provided silyl ether (+)-4 (20 mg,

91%) as a colorless oil: [α]²_D⁰+36.0 (c 0.8, CHCl₃); IR (neat) 2954, 2928,

2896, 2857, 1725, 1594, 1472, 1250, 1108, 1063 cm⁻¹; ¹H NMR (500

MHz, CDCl₃) δ 6.93 (s, 1H), 5.45 (d, J = 9.7 Hz, 1H), 5.32 (dab, J = 7.0

Hz, 1H), 5.27 (dab, J = 6.7 Hz, 1H), 5.27 (s, 1H), 4.82 (d, J = 9.6 Hz,

1H), 4.23−4.07 (m, 3H), 4.00 (d, J = 8.7 Hz, 1H), 3.88−3.78 (m, 2H),

3.75 (dd, J = 8.7, 7.9 Hz, 2H), 3.58 (dd, J = 3.8, 3.8 Hz, 1H), 3.37 (s, 3H),

3.34 (d, J = 11.6 Hz, 1H), 3.09 (d, J = 15.3 Hz, 1H), 2.64 (dd, J = 16.4,

12.1 Hz, 1H), 2.32−2.22 (m, 1H), 2.12 (s, 3H), 2.03−1.92 (m, 1H),

1.87−1.77 (m, 1H), 1.62 (dd, J = 11.6, 11.6 Hz, 1H), 1.48 (ddd, J = 13.7,

8.2, 8.2 Hz, 1H), 1.07 (d, J = 6.7 Hz, 3H), 0.97 (s, 3H), 0.9−0.93 (m,

6H), 0.91 (s, 9H), 0.86 (s, 3H), 0.80 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H),

0.06 (s, 3H), 0.01 (s, 3H), 0.00 (s, 9H), 0.00 (s, 18H); ¹³C NMR (125

MHz, CDCl₃) δ 163.5, 159.8, 159.1, 157.2, 141.4, 117.2, 109.5, 102.3,

94.5, 93.1, 84.4, 79.9, 77.7, 77.2, 73.6, 68.9, 67.8, 66.8, 66.7, 63.6, 56.1,

39.9, 37.6, 32.9, 31.7, 29.9, 26.8, 26.2, 26.0, 18.4, 18.3, 18.3, 18.2, 17.8,

11.4, 9.1, −1.1, −1.2, −1.3, −3.3, −4.2, −4.7, −4.7; high resolution mass

spectrum (ES+) m/z 1108.6233 [(M + Na)⁺; calcd for

C₅₃H₁₀₃NO₁₂Si₅Na 1108.6225].

Amide (+)-32. A solution of acid (−)-3 (47 mg, 4 equiv) in CH₂Cl₂

(1.5 mL) was cooled to 0 °C, and i-Pr₂NEt (30 μL, 1.1 equiv) was added

followed by trimethylacetyl chloride (20 μL, 1.05 equiv). After 30 min at

0 °C, sat. NH₄Cl (3 mL) was added followed by enough H₂O to dissolve

any solids. The layers were separated, and the aqueous layer extracted

with CH₂Cl₂(3 × 5 mL). The combined organic layers were then dried

over MgSO₄and concentrated. The unpuriﬁed mixed anhydride 31 was

azeotroped with benzene (3 × 3 mL), placed on the vacuum pump for

30 min, and then dissolved in THF (0.4 mL). A solution of (+)-4 (41.5

mg, 0.038 mmol) in THF (0.4 mL) was cooled to −78 °C, and LiHMDS

(0.152 mL, 0.5 M in THF, 2.0 equiv) was added dropwise over 1 min.

The solution was stirred for 30 min at −78 °C, and then the solution of

mixed anhydride 32 was added dropwise over 5 min. The reaction was

stirred at −78 °C for 45 min and then warmed to −60 °C and stirred for

30 min. Sat. NH₄Cl (2 mL) was added, and the reaction allowed to warm

to rt. The reaction was extracted with CH₂Cl₂(4 × 5 mL). The

combined organic layers were then dried over MgSO₄and evaporated.

Preparative chromatography (20% EtOAc/hexanes, 1000 μm plate)

provided amide (+)-32 (41.2 mg, 79% yield) as a colorless oil: [α]_D²⁰

+40.2 (c 0.4, CHCl₃); IR (neat) 2953, 2896, 2857, 1726, 1591, 1467,

1250, 1110, 1063 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 6.92 (s, 1H),

5.66 (d, J = 4.6 Hz, 1H), 5.34−5.25 (m, 4H), 5.17 (d, J = 4.9 Hz, 1H),

4.77 (d, J = 11.5 Hz, 2H), 4.63 (dd, J = 23.1, 6.6 Hz, 2H), 4.33−4.27 (m,

2H), 4.20 (ddd, J = 12.1, 8.4, 2.0 Hz, 1H), 4.12 (ddd, J = 10.0, 2.9, 2.9 Hz,

1H), 3.90−3.78 (m, 2H), 3.78−3.73 (m, 2H), 3.65−3.59 (m, 1H),

3.59−3.49 (m, 3H), 3.34 (s, 3H), 3.28 (s, 3H), 3.14 (d, J = 9.6 Hz, 1H),

3.10 (dd, J = 16.5, 2.0 Hz, 1H), 2.93 (dd, J = 16.4, 12.6 Hz, 1H), 2.30 (dd,

J = 14.7, 9.0 Hz, 1H), 2.22 (d, J = 12.7 Hz, 1H), 2.19 (s, 3H), 2.07−1.96

(m, 2H), 1.81 (dd, J = 14.0, 10.3 Hz, 1H), 1.75 (s, 3H), 1.69 (ddd, J =

13.2, 10.8, 6.5 Hz, 1H), 1.61 (ddd, J = 13.6, 9.5, 3.2 Hz, 2H), 1.10 (d, J =

6.6 Hz, 3H), 1.10−1.04 (m, 2H), 1.00−0.93 (m, 4H), 0.90 (s, 12H),

0.87−0.80 (m, 2H), 0.83 (s, 3H), 0.78 (s, 9H), 0.05 (s, 15H), 0.04 (s,

3H), 0.01 (s, 9H), 0.00 (s, 9H), −0.02 (s, 3H), −0.05 (s, 9H); ¹³C NMR

(125 MHz, CDCl₃) δ 174.9, 163.7, 159.8, 159.1, 154.5, 142.9, 142.1,

117.5, 113.0, 109.5, 102.2, 95.3, 94.5, 93.1, 88.5, 81.3, 80.2, 75.7, 74.9,

73.0, 69.3, 66.8, 66.8, 66.3, 66.1, 58.3, 56.8, 40.7, 39.2, 39.1, 35.3, 30.5,

30.0, 28.7, 26.1, 26.0, 24.2, 23.1, 18.3, 18.3, 18.3, 18.2, 17.8, 13.6, 11.4,

9.1, −1.2, −1.2, −1.3, −1.4, −3.1, −4.0, −4.5, −4.7.; high resolution

mass spectrum (ES+) m/z 1394.7849 [(M + Na)⁺; calcd for

C₆₇H₁₂₉NO₁₆Si₆Na 1394.7825].

Irciniastatin A (+)-1. Compound (+)-32 (9.8 mg, 7.1 μmol) was

dissolved in DMF (0.16 mL), and TASF (30 mg, 15 equiv) was added.

The reaction was heated to 50 °C. After 48 h, the reaction was diluted

with EtOAc, and sat. NH₄Cl (1 mL) was added followed by enough

H₂O (0.5 mL) to dissolve any solids. The reaction was extracted with

M

dx.doi.org/10.1021/jo400260m | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

EtOAc (4 × 2 mL). The combined organic layers were then dried over

MgSO₄and evaporated. Preparative TLC (70% EtOAc/hexanes, 500

μm plate) provided (+)-1, irciniastatin A (1.7 mg), along with a

monoprotected compound (SEM group on one of the phenolic

oxygens). The monoprotected compound was dissolved in Et₂O (0.3

mL), and MeNO₂(20 μL) was added followed by MgBr₂(13 mg, 20

equiv). After stirring for 15 min at rt, the reaction was diluted with

EtOAc (2 mL), and sat. NaHCO₃(1 mL) was added. The reaction was

extracted with EtOAc (5 × 1 mL), and the combined organic layers were

then dried over MgSO₄and concentrated. Preparative TLC (60%

EtOAc/hexanes, 500 μm plate) provided an additional 1.5 mg of the

natural product to give a total of 3.2 mg (74% yield, 2 steps) of (+)-1

(irciniastatin A): [α]²_D⁰+21.0 (c 0.1, CHCl₃); IR (neat) 3366, 2965,

2928, 2853, 1654, 1515, 1459, 1381, 1254, 1173, 1107, 1067 cm⁻¹; ¹H

NMR (500 MHz, CD₃OD) δ 6.25 (s, 1H), 5.38 (d, J = 8.2 Hz, 1H), 4.74

(s, 1H), 4.72 (s, 1H), 4.49 (ddd, J = 12.2, 5.9, 3.1 Hz, 1H), 4.35 (d, J = 2.6

Hz, 1H), 3.97−3.92 (m, 2H), 3.67 (ddd, J = 9.3, 3.4, 2.7 Hz, 1H), 3.59

(dd, J = 10.9, 4.5 Hz, 1H), 3.50 (dd, J = 10.1, 1.3 Hz, 1H), 3.35 (s, 3H),

3.21 (s, 3H), 3.13 (dd, J = 16.7, 3.1 Hz, 1H), 2.86 (dd, J = 16.7, 12.2 Hz,

1H), 2.35 (dd, J = 14.6, 9.3 Hz, 1H), 2.11 (dd, J = 14.1, 3.6 Hz, 2H), 2.10

(s, 3H), 2.02 (ddd, J = 13.6, 4.3, 2.8 Hz, 1H), 1.91 (ddddd, J = 6.9, 6.9,

6.9, 6.9, 2.7 Hz, 1H), 1.77 (ddd, J = 13.7, 11.1, 6.3 Hz, 2H), 1.72 (s, 3H),

1.68 (ddd, J = 14.5, 3.2, 1.9 Hz, 2H), 1.10 (d, J = 7.0, 3H), 0.97 (s, 3H),

0.90 (s, 3H); ¹³C NMR (125 MHz, CD₃OD) δ 176.3, 172.5, 164.7,

163.8, 144.0, 141.3, 115.4, 113.1, 101.6, 101.5, 82.8, 82.3, 82.1, 79.9,

74.2, 73.6, 73.4, 72.2, 57.8, 56.7, 43.4, 39.9, 38.8, 34.5, 30.6, 29.6, 23.8,

23.0, 14.1, 10.9, 9.3; high resolution mass spectrum (ES+) m/z 632.3038

[(M + Na)⁺; calcd for C₃₁H₄₇NO₁₁Na 632.3047].

Aldehyde 35. To a 0 °C solution of diol 37 (0.50 g, 4.8 mmol) in

THF (24 mL) was added 60% NaH (0.19 g, 1.0 equiv) in three equal

portions over 5 min. After 10 min, TBSCl (0.72 g, 1 equiv) dissolved in

THF (5 mL) was added dropwise. After 4 h, the reaction was quenched

with MeOH (2 mL). Sat. NaHCO₃(15 mL) was added, and the reaction

extracted with CH₂Cl₂(3 × 10 mL). The combined organic layers were

then dried over MgSO₄and concentrated. Flash chromatography (10%

EtOAc/hexanes) provided TBS ether 66 (0.93 g, 89% yield) as a

colorless oil: IR (neat) 3389, 2955, 2929, 2858, 1472, 1254, 1096, 1047

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 3.46 (s, 4H), 2.86 (dd, J = 5.5, 5.5

Hz, 1H), 0.90 (s, 9H), 0.88 (s, 6H), 0.06 (s, 6H); ¹³C NMR (125 MHz,

CDCl₃) δ 73.0, 72.5, 36.6, 26.0, 21.7, 18.4, −5.4; high resolution mass

spectrum (CI+) m/z 219.1794 [(M + H)⁺; calcd for C₁₁H₂₇O₂Si

219.1780].

To a 0 °C solution of TBS ether 66 (1.51 g, 6.91 mmol) in DMSO

(4.9 mL, 10 equiv) and CH₂Cl₂(35 mL) was added Et₃N (2.89 mL, 3

equiv) followed by SO₃·pyridine (3.25 g, 3 equiv). After 1 h, brine (20

mL) and H₂O (5 mL) were added. The layers were separated, and the

aqueous layer was extracted with CH₂Cl₂(3 × 20 mL). The combined

organic layers were then dried over MgSO₄and concentrated. Flash

chromatography (5% EtOAc/hexanes to 10% EtOAc/hexanes)

provided aldehyde 35 (1.43 g, 96% yield) as a light yellow oil: IR

(neat) 2956, 2930, 2893, 2858, 1733, 1472, 1257, 1104 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) δ 9.55 (s, 1H), 3.58 (s, 2H), 1.03 (s, 6H), 0.85 (s,

9H), 0.02 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 206.3, 68.6, 48.3,

26.0, 18.7, 18.4, −5.4; high resolution mass spectrum (CI+) m/z

215.1453 [(M − H)⁺; calcd for C₁₁H₂₃O₂Si 215.1468].

Alcohol (+)-34. To a suspension of N-Ts-^L-tryptophan (5.15 g, 1.2

equiv) in CH₂Cl₂(150 mL) was added Cl₂BPh (1.87 mL, 1.2 equiv)

dropwise. After 2 h at rt, the mixture was concentrated in vacuo, n-

butyronitrile (50 mL) added, and the solution cooled to −78 °C. A

mixture of aldehyde 35 (2.6 g, 12.0 mmol), ketene acetal 36 (3.86 g, 1.5

equiv), and isopropanol (1.38 mL, 1.5 equiv) in n-butyronitrile (15 mL)

was added over 2 h via syringe pump. After an additional 2 h at −78 °C,

the solution was warmed to 0 °C over 30 min, followed by addition of

sat. NaHCO₃(20 mL) and brine (20 mL). The resulting solution was

extracted with Et₂O (3 × 30 mL). The combined organic layers were

then dried over MgSO₄and evaporated. Flash chromatography (5%

EtOAc/hexanes to 10% EtOAc/hexanes to 15% EtOAc/hexanes)

provided (+)-34 (2.49 g, 66% yield) as a colorless oil and a single

enantiomer, as determined by Mosher ester analysis: [α]²_D⁰+27.9 (c 0.6,

CHCl₃); IR (neat) 3486, 2953, 2929, 2858, 1726, 1657, 1471, 1258,

1092 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.10 (ddd, J = 15.6, 7.2, 7.2,

Hz, 1H), 5.91 (ddd, J = 15.7, 1.5, 1.5, Hz, 1H), 3.75 (d, J = 3.2, 1H), 3.71

(s, 3H), 3.63 (ddd, J = 10.0, 2.9, 2.9 Hz, 1H), 3.49 (d, J = 2.0 Hz, 2H),

2.37 (dd, J = 14.5, 6.8 Hz, 1H), 2.26 (dddd, J = 14.6, 10.0, 7.5, 1.4 Hz,

1H), 0.91 (s, 3H), 0.89 (s, 9H), 0.85 (s, 3H), 0.07 (s, 6H); ¹³C NMR

(125 MHz, CDCl₃) δ 167.1, 147.9, 122.6, 78.3, 73.6, 51.6, 38.6, 35.5,

26.0, 22.6, 19.0, 18.3, −5.4, −5.5; high resolution mass spectrum (ES+)

m/z 317.2137 [(M + H)⁺; calcd for C₁₆H₃₃O₄Si 317.2148].

Epoxide (+)-38. To a 0 °C solution of (+)-34 (0.226 g, 0.714 mmol)

in CH₂Cl₂(7.1 mL) was added 2,6-lutidine (0.164 mL, 2.0 equiv)

followed by dropwise addition of TBSOTf (0.246 mL, 1.5 equiv). After 1

h, sat. NaHCO₃(5 mL) was added, and the layers separated. The

aqueous layer was extracted with CH₂Cl₂(3 × 10 mL), and the

combined organic layers were dried over MgSO₄and concentrated.

Flash chromatography (2% EtOAc/hexanes to 5% EtOAc/hexanes)

provided TBS ether (+)-67 (0.269 g, 96% yield) as a colorless oil: [α]_D²⁰

+3.6 (c 1.0, CHCl₃); IR (neat) 2955, 2930, 2886, 2857, 1730, 1657,

1472, 1257, 1090 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.12−6.92 (m,

1H), 5.81 (ddd, J = 15.7, 1.5, 1.5 Hz, 1H), 3.74 (dd, J = 6.4, 4.4 Hz, 1H),

3.72 (s, 3H), 3.28 (dab, J = 9.5 Hz, 1H), 3.26 (dab, J = 9.6 Hz, 1H), 2.48

(dddd, J = 15.0, 6.4, 4.4, 1.7 Hz, 1H), 2.36−2.27 (m, 1H), 0.89 (s, 9H),

0.83 (s, 3H), 0.79 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H), 0.01 (s, 6H); ¹³C

NMR (125 MHz, CDCl₃) δ 167.1, 148.9, 122.0, 75.1, 69.7, 51.6, 41.1,

36.6, 26.2, 26.1, 21.3, 20.9, 18.5, 18.4, −3.5, −4.1, −5.2, −5.3; high

resolution mass spectrum (ES+) m/z 431.2997 [(M + H)⁺; calcd for

C₂₂H₄₇O₄Si₂431.3013].

A solution of TBS ether (+)-67 (0.217 g, 0.504 mmol) in CH₂Cl₂(10

mL) was cooled to −78 °C, and DIBAL-H (1.06 mL, 1.0 M in hexanes,

2.1 equiv) was slowly added. After 5 min, the reaction was quenched

with MeOH (0.5 mL) and allowed to warm to rt. Sat. Rochelle’s salt (10

mL) and EtOAc (10 mL) were added, and the solution stirred for 1 h.

H₂O (10 mL) was then added to dissolve the suspended solids, and the

layers were separated. The aqueous layer was extracted with EtOAc (3 ×

10 mL), and the combined organic layers were dried over MgSO₄and

concentrated. Flash chromatography (5% EtOAc/hexanes to 10%

EtOAc/hexanes) provided allylic alcohol (−)-68 (0.237 g, 99%) as a

colorless oil: [α]²_D⁰−3.4 (c 1.0, CHCl₃); IR (neat) 3327, 2955, 2929,

2892, 2857, 1715, 1472, 1254, 1091, 1006 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 5.82−5.57 (m, 2H), 4.09 (d, J = 5.7, 2H), 3.64 (dd, J = 6.3, 4.3

Hz, 1H), 3.33 (dab, J = 9.5 Hz, 1H), 3.28 (dab, J = 9.5 Hz, 1H), 2.36

(ddd, J = 14.7, 4.8, 4.8 Hz, 1H), 2.16 (ddd, J = 14.5, 7.1, 7.1 Hz, 1H), 0.89

(s, 21H), 0.80 (s, 3H), 0.04 (s, 3H), 0.02 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) δ 132.3, 130.1, 75.9, 69.9, 64.1, 41.2, 36.5, 26.3, 26.2, 21.4, 20.8,

18.5, 18.4, −3.2, −4.1, −5.2, −5.3; high resolution mass spectrum (ES+)

m/z 403.3065 [(M + H)⁺; calcd for C₂₁H₄₇O₃Si₂403.3063].

To freshly activated 3 Å molecular sieves (0.2 g) was added

(−)-DIPT (15 μL, 0.24 equiv) in CH₂Cl₂(0.5 mL). The solution was

cooled to −20 °C, and Ti(Oi-Pr)₄(18 μL, 0.2 equiv) in CH₂Cl₂(0.5

mL) was added followed by t-BuOOH (0.176 mL, 5 M in decane, 3.0

equiv). The reaction was stirred for 30 min, and then allylic alcohol

(−)-68 (0.118 g, 0.293 mmol) dissolved in CH₂Cl₂(1 mL) was added

via syringe. The ﬂask and syringe were rinsed with CH₂Cl₂(0.4 mL) into

the reaction ﬂask. After 4 h, 10% aq. citric acid (2 mL) was added, and

the reaction warmed to rt. After 1 h at rt, brine (3 mL) was added, the

layers were separated, and the aqueous layer extracted with EtOAc (3 ×

5 mL). The combined organic layers were dried over MgSO₄and

concentrated. Flash chromatography (5% EtOAc/hexanes to 10%

EtOAc/hexanes to 15% EtOAc/hexanes) provided epoxide (+)-38

(0.108 g, 88% yield, 13:1 inseparable mixture of epoxides) as a colorless

oil: [α]²_D⁰+24.3 (c 1.0, CHCl₃); IR (neat) 3430, 2955, 2929, 2895, 2857,

1472, 1254, 1091, 1009 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 3.91 (ddd,

J = 12.5, 5.4, 2.4 Hz, 1H), 3.80 (dd, J = 7.4, 3.8 Hz, 1H), 3.60 (ddd, J =

12.5, 7.2, 4.4 Hz, 1H), 3.35 (dab, J = 9.6 Hz, 1H), 3.28 (dab, J = 9.6 Hz,

1H), 3.12 (ddd, J = 6.9, 4.5, 2.3 Hz, 1H), 2.93 (ddd, J = 4.6, 2.4, 2.4 Hz,

1H), 1.80 (dd, J = 7.1, 5.8 Hz, 1H), 1.79−1.72 (m, 1H), 1.65 (ddd, J =

14.6, 7.0, 3.8 Hz, 1H), 0.90 (s, 9H), 0.89 (s, 9H), 0.83 (s, 3H), 0.79 (s,

3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.01 (s, 6H); ¹³C NMR (125 MHz,

CDCl₃) δ 73.7, 69.7, 61.9, 60.1, 54.1, 40.7, 35.5, 26.3, 26.1, 21.5, 20.5,

18.6, 18.5, −3.8, −4.0, −5.2, −5.3; high resolution mass spectrum (ES+)

m/z 441.2846 [(M + Na)⁺; calcd for C₂₁H₄₆O₄Si₂Na 441.2833].

N

dx.doi.org/10.1021/jo400260m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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Ester (+)-39. Alcohol (+)-38 (0.199 g, 0.474 mmol) in CH₃CN (4.7

mL) was treated with TEMPO (6 mg, 0.08 equiv) followed by addition

of pH 7 buﬀer (4.7 mL). The reaction was then treated with NaClO₂,

followed by dropwise addition of NaOCl (0.18 mL, 5% aq. solution).

After 2 h, sodium sulﬁte (200 mg, 3.3 equiv) was added, and the reaction

stirred for 30 min, where the solution turned from a light orange color to

colorless. The reaction was acidiﬁed to pH 4 with 10% aq. citric acid and

extracted with EtOAc (5 × 10 mL). The combined organic layers were

dried over MgSO₄and concentrated to yield carboxylic acid, which was

carried forward without further puriﬁcation.

for 5 h, the solution was warmed to −40 °C over 1 h and held at −40 °C.

After 12 h, the reaction was warmed to 0 °C, and a 1:1:1 mixture of

MeOH/pH 7 buﬀer/30% aq. H₂O₂(1 mL) was added. After 1 h, sat.

Na₂S₂O₃(4 mL) was added very slowly over 30 min to destroy any

remaining peroxides. The reaction was then extracted with CH₂Cl₂(3 ×

10 mL). The combined organic layers were dried over MgSO₄and

concentrated. Flash chromatography (10% EtOAc/hexanes to 15%

EtOAc/hexanes to 20% EtOAc/hexanes) provided the aldol product

(0.020 g, 86% yield) as a 5:1 mixture of diastereomers.

The aldol products were dissolved in CH₂Cl₂(1 mL), and CSA (2.3

mg, 0.2 equiv) was added. After 2 h, sat. NaHCO₃(2 mL) added, and the

reaction stirred for 5 min. The layers were separated, and the aqueous

layer was extracted with CH₂Cl₂(3 × 5 mL). The combined organic

layers were dried over MgSO₄and concentrated. Flash chromatography

(10% EtOAc/hexanes to 15% EtOAc/hexanes to 20% EtOAc/hexanes)

provided (+)-41 (14.8 mg, 60% yield over 2 steps for the major

diastereomer) and (−)-42 (2.9 mg, 12% yield over 2 steps for the minor

diastereomer). Major diastereomer (+)-41: [α]²_D⁰+9.8 (c 0.5, CHCl₃);

IR (neat) 2954, 2930, 2861, 1741, 1714, 1461, 1388, 1366, 1258, 1074

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 4.26 (dd, J = 6.3, 4.2 Hz, 1H), 4.15

(ddd, J = 8.0, 3.8, 3.8 Hz, 1H), 4.06 (dd, J = 10.0, 3.5 Hz, 1H), 3.78 (s,

3H), 3.64 (dd, J = 5.0, 3.3 Hz, 1H), 2.93 (d, J = 6.3 Hz, 1H), 2.57 (dd, J =

15.6, 3.6 Hz, 1H), 2.50−2.42 (m, 2H), 2.05 (ddd, J = 13.5, 9.3, 3.2 Hz,

1H), 1.45−1.38 (m, 1H), 1.40−1.36 (m, 1H), 1.05 (dd, J = 7.3, 7.3 Hz,

3H), 1.00 (s, 3H), 0.92 (s, 9H), 0.85 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 210.8, 173.3, 77.7, 73.5, 73.4, 68.8, 52.7,

42.4, 37.5, 36.9, 29.8, 26.0, 25.8, 20.7, 18.2, 7.9, −4.4, −4.8; high

resolution mass spectrum (ES+) m/z 425.2330 [(M + Na)⁺; calcd for

C₂₀H₃₈O₆SiNa 425.2336]. Minor diastereomer (−)-42: [α]²_D⁰−38.7 (c

0.8, CHCl₃); IR (neat) 3480, 2955, 2930, 2885, 2857, 1741, 1719, 1255,

1096, 1060, 1008 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 4.24 (dd, J = 6.0,

3.3 Hz, 1H), 4.17 (dd, J = 10.5, 2.3 Hz, 1H), 4.08 (ddd, J = 12.2, 2.7, 2.7

Hz, 1H), 3.75 (s, 3H), 3.55 (dd, J = 2.7, 2.7 Hz, 1H), 2.79 (d, J = 6.1 Hz,

1H), 2.59−2.40 (m, 3H), 2.25 (dd, J = 14.9, 2.4 Hz, 1H), 2.04 (ddd, J =

14.2, 12.2, 2.4 Hz, 1H), 1.22 (ddd, J = 13.4, 3.0, 3.0 Hz, 1H), 1.04 (dd, J =

7.3, 7.3 Hz, 3H), 0.91 (s, 9H), 0.87 (s, 3H), 0.81 (s, 3H), 0.04 (s, 3H),

0.01 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 210.8, 172.9, 76.3, 74.9,

73.9, 73.4, 52.6, 42.8, 37.4, 37.2, 30.0, 26.0, 23.7, 19.7, 18.3, 7.8, −4.4,

−4.7; high resolution mass spectrum (ES+) m/z 425.2336 [(M + Na)⁺;

calcd for C₂₀H₃₈O₆SiNa 425.2336].

Tetrahydropyran (+)-6. To a 0 °C solution of (+)-41 (14.8 mg,

0.036 mmol) in CH₂Cl₂(0.18 mL) was added proton sponge (95 mg,

12.0 equiv) followed by Me₃O·BF₄(54 mg, 10 equiv). The reaction was

then stirred at rt. After 4 h, 10% aq. citric acid (2 mL) was added. The

layers were separated, and the aqueous layer extracted CH₂Cl₂(3 × 5

mL). The combined organic layers were washed with 10% aq. citric acid

(4 mL) and then brine (4 mL). The organic layer was then dried over

MgSO₄and concentrated. Flash chromatography (10% EtOAc/

hexanes) provided (+)-6 (14.2 mg, 92% yield) as a colorless oil. All

spectral data matched that of the ketone fragment constructed during

the ﬁrst-generation approach: [α]²_D⁰+16.5 (c 1.7, CHCl₃); IR (neat)

2954, 2934, 2886, 2858, 1754, 1722, 1712, 1462, 1361, 1255, 1119, 1073

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) 4.08 (dd, J = 11.3, 6.0 Hz, 1H), 3.99

(dd, J = 9.6, 3.0 Hz, 1H), 3.90 (d, J = 6.4 Hz, 1H), 3.73 (s, 3H), 3.62 (dd,

J = 7.5, 3.6 Hz, 1H), 3.40 (s, 3H), 2.91 (dd, J = 15.2, 9.7 Hz, 1H), 2.56−

2.29 (m, 3H), 1.93 (ddd, J = 13.8, 6.1, 3.9 Hz, 1H) 1.60 (ddd, J = 12.7,

9.0, 5.3 Hz, 1H), 1.03 (dd, J = 7.3, 7.3 Hz, 3H), 0.96 (s, 3H), 0.90 (s,

9H), 0.83 (s, 3H), 0.04 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 210.4,

171.7, 82.5, 77.4, 73.1, 69.8, 58.8, 52.2, 42.6, 38.1, 37.2, 30.3, 26.0, 25.1,

18.2, 17.9, 7.8, −4.2, −4.8; high resolution mass spectrum (ES+) m/z

439.2491 [(M + Na)⁺; calcd for C₂₁H₄₀O₆SiNa 439.2492].

The unpuriﬁed acid was dissolved in CH₂Cl₂(2.4 mL) and MeOH

(2.4 mL). The solution was cooled to 0 °C, and TMS−diazomethane

(0.28 mL, 2 M in Et₂O, 1.2 equiv) was added dropwise until the solution

remained yellow in color. Argon gas was bubbled through the reaction

for 10 min, and then the solvent evaporated. Flash chromatography (5%

EtOAc/hexanes) provided ester (+)-39 (0.195 g, 91% yield, 2 steps) as a

colorless oil: [α]²_D⁰+15.8 (c 1.0, CHCl₃); IR (neat) 2955, 2930, 2887,

2857, 1759, 1472, 1254, 1201, 1089, 1006 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 3.81 (dd, J = 7.4, 3.8 Hz, 1H), 3.75 (s, 3H), 3.34 (dab, J = 9.6

Hz, 1H), 3.30 (ddd, J = 6.5, 4.5, 1.9 Hz, 1H), 3.28 (dab, J = 9.6 Hz, 1H),

3.22 (d, J = 1.9 Hz, 1H), 1.80 (ddd, J = 14.6, 7.4, 4.5 Hz, 1H), 1.67 (ddd, J

= 14.7, 6.8, 3.8 Hz, 1H), 0.90 (s, 9H), 0.88 (s, 9H), 0.83 (s, 3H), 0.78 (s,

3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.01 (s, 6H); ¹³C NMR (125 MHz,

CDCl₃) δ 169.9, 73.6, 69.6, 56.9, 54.6, 52.5, 40.7, 35.5, 26.3, 26.1, 21.3,

20.7, 18.6, 18.5, −3.8, −4.0, −5.2, −5.3; high resolution mass spectrum

(ES+) m/z 469.2778 [(M + Na)⁺; calcd for C₂₂H₄₆O₅Si₂Na 469.2782].

Aldehyde (+)-40. To bis-silyl ether (+)-39 (72.0 mg, 0.159 mmol)

was added a HF·pyridine/pyridine/THF solution (0.64 mL, 10 equiv

HF, stock solution made up of 0.5 mL of HF·pyridine, 1.0 mL of

pyridine, and 5.0 mL of THF). After stirring 20 h at rt, sat. NaHCO₃(5

mL) was added slowly. Once all gas evolution had ceased, the reaction

was extracted with CH₂Cl₂(3 × 5 mL). The combined organic layers

were dried over MgSO₄and concentrated. Flash chromatography (5%

EtOAc/hexanes to 10% EtOAc/hexanes to 15% EtOAc/hexanes to 20%

EtOAc/hexanes) provided alcohol (+)-69 as a single diastereomer (37.2

mg, 72% yield) as a colorless oil: [α]²_D⁰+46.8 (c 0.5, CHCl₃); IR (neat)

3465, 2955, 2930, 2857, 1744, 1446, 1290, 1253, 1205, 1089, 1051, 1004

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 3.80 (dd, J = 7.4, 3.8 Hz, 1H), 3.77

(s, 3H), 3.59 (d, J = 10.9 Hz, 1H), 3.36−3.27 (m, 2H), 3.26 (d, J = 1.7

Hz, 1H), 2.37 (s, 1H), 1.95 (ddd, J = 14.8, 7.4, 3.9 Hz, 1H), 1.67 (ddd, J

= 14.8, 7.3, 3.8 Hz, 1H), 0.99 (s, 3H), 0.91 (s, 9H), 0.81 (s, 3H), 0.14 (s,

3H), 0.14 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.6, 76.7, 70.0,

56.6, 54.5, 52.7, 39.6, 35.6, 26.2, 23.0, 21.5, 18.4, −3.9, −4.0; high

resolution mass spectrum (ES+) m/z 355.1908 [(M + Na)⁺; calcd for

C₁₆H₃₂O₅SiNa 355.1917].

To a solution of alcohol (+)-69 (0.025 g, 0.075 mmol) in CH₂Cl₂

(0.75 mL) and DMSO (0.75 mL) at 0 °C was added Et₃N (0.105 mL, 10

equiv) followed by SO₃·pyridine (0.047 g, 4 equiv) in one portion. After

2 h, sat. NaHCO₃(4 mL) was added, and the layers separated. The

aqueous layer was extracted with CH₂Cl₂(3 × 5 mL), and the combined

organic layers were dried over MgSO₄and concentrated. Flash

chromatography (5% EtOAc/hexanes to 10% EtOAc/hexanes to 20%

EtOAc/hexanes) provided aldehyde (+)-40 (23.5 mg, 95% yield) as a

light yellow oil: [α]²_D⁰+22.9 (c 0.5, CHCl₃); IR (neat) 2955, 2931, 2857,

1754, 1448, 1291, 1254, 1205, 1093 cm⁻¹; ¹H NMR (500 MHz, CDCl₃)

δ 9.56 (s, 1H), 4.06 (dd, J = 7.9, 3.6 Hz, 1H), 3.77 (s, 3H), 3.28 (ddd, J =

7.5, 3.8, 1.9 Hz, 1H), 3.24 (d, J = 1.9 Hz, 1H), 1.90 (ddd, J = 14.6, 7.9, 3.8

Hz, 1H), 1.54 (ddd, J = 14.7, 7.5, 3.6 Hz, 1H), 1.06 (s, 3H), 1.02 (s, 3H),

0.88 (s, 9H), 0.13 (s, 3H), 0.08 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

205.8, 169.4, 73.7, 56.0, 54.4, 52.7, 51.3, 35.7, 26.1, 19.3, 18.4, 17.7, −3.9,

−4.0; high resolution mass spectrum (ES+) m/z 353.1753 [(M + Na)⁺;

calcd for C₁₆H₃₀O₅SiNa 353.1761].

Aldehyde 45. To a solution of bis-phenol 14 (519 mg, 2.043 mmol)

in acetone (25.0 mL) was added K₂CO₃(1.03 g, 7.452 mmol, 3.7 equiv)

followed by dropwise addition of a solution of 3,4-dimethoxybenzyl-

bromide (2.0 mL, 2.2 M in acetone, 2.2 equiv). The yellow reaction

mixture was stirred for 24 h and quenched with H₂O (20 mL). The

layers were separated, and the aqueous layer was extracted with EtOAc

(3 × 20 mL). The combined organic layers were dried over MgSO₄,

ﬁltered and concentrated in vacuo. The crude mixture was puriﬁed via

ﬂash chromatography (40% EtOAc:hexanes to 50% EtOAc:hexanes) to

Tetrahydropyran (+)-41. To a solution of (−)-DIPCl (0.035 g, 1.8

equiv) in Et₂O (0.4 mL) cooled to −78 °C was added Et₃N (0.021 mL,

2.5 equiv) followed by slow dropwise addition of 2-butanone (0.010 mL,

1.8 equiv). The solution immediately turned cloudy white. After stirring

for 2 h at −78 °C, aldehyde (+)-40 (0.020 g, 0.061 mmol) was dissolved

in Et₂O (0.4 mL) and added dropwise to the boron enolate over 5 min

via syringe. The ﬂask and syringe were then rinsed with Et₂O (0.4 mL),

and the rinse added to the reaction over 2 min. After stirring at −78 °C

O

dx.doi.org/10.1021/jo400260m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

provide bis-DMB ether 70 (850 mg, 1.532 mmol, 75%) as a colorless

solid: mp 102.0−103.0 °C; IR (neat) 2947, 1732, 1594, 1515, 1459,

1264, 1152, 1025 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) 6.97−6.81 (m, 6

H), 6.52 (s, 1 H), 4.99 (s, 2 H), 4.95 (s, 2 H), 3.89 (s, 3 H), 3.88 (s, 3 H),

3.88 (s, 3 H), 3.87 (s, 3 H), 3.83 (s, 3 H), 3.69 (s, 2 H), 3.67 (s, 3 H), 2.14

(s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 171.2, 158.7, 155.2, 149.4,

149.3, 149.1, 148.9, 132.7, 129.6, 129.4, 120.0, 119.7, 119.6, 117.8, 111.3,

111.1, 110.9, 110.1, 98.3, 71.2, 70.7, 56.1, 56.1, 56.1, 56.0, 52.2, 36.2,

11.7; HRMS (ES+) m/z 577.2047 [(M + Na)⁺; calcd for C₃₀H₃₄O₁₀Na

577.2050].

A solution of bis-DMB ether 70 (850 mg, 1.53 mmol) in CH₂Cl₂

(15.3 mL) was cooled to −78 °C, and DIBAL-H (2.1 mL, 1.0 M in

hexanes, 1.4 equiv) was added over 20 min via syringe pump. The

reaction mixture was allowed to stir for an additional 5 min before it was

quenched by the addition of MeOH (7.0 mL) and was warmed to room

temperature and then diluted with EtOAc (2 mL) and a saturated aq.

solution of Rochelle’s salt (2 mL). The biphasic reaction mixture was

allowed to stir for 1 h at room temperature to allow the organic layer to

transition from cloudy to clear. The layers were separated, and the

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

organic layers were dried over MgSO₄, ﬁltered and concentrated in

vacuo. The crude mixture was puriﬁed via ﬂash chromatography (40%

EtOAc/hexanes to 50% EtOAc/hexanes) to provide aldehyde 45 (697

mg, 1.33 mmol, 87%) as a colorless solid: mp 122.5−124.0 °C; IR (neat)

2944, 2838, 2726, 1722, 1594, 1515, 1459, 1265, 1153, 1030 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) 9.65 (t, J = 1.8 Hz, 1 H), 6.97 (d, J = 1.7 Hz, 1

H), 6.94−6.83 (m, 5 H), 6.55 (s, 1 H), 5.02 (s, 2 H), 4.97 (s, 2 H), 3.90

(s, 3 H), 3.89 (s, 9 H), 3.84 (s, 3 H), 3.68 (d, J = 1.6 Hz, 2 H), 2.10 (s, 3

H); ¹³C NMR (125 MHz, MeOD) δ 198.6, 168.7, 158.9, 155.4, 149.4,

149.4, 149.2, 149.0, 131.0, 129.4, 129.2, 120.1, 119.8, 119.7, 118.0, 111.3,

111.1, 110.0, 110.7, 98.5, 71.2, 70.7, 56.3, 56.1, 56.1, 56.1, 52.3, 46.1,

11.9; HRMS (ES+) m/z 525.2141 [(M + Na)⁺; calcd for C₂₉H₃₃O₉

525.2125].

β-Hydroxy Ketone (+)-46. A solution of ketone (+)-6 (114 mg,

0.274 mmol, azeotroped × 3 with benzene, placed under a high vacuum

overnight) in CH₂Cl₂(1.35 mL) was cooled to −78 °C, and Cl₂BPh

(0.05 mL, 0.383 mmol, 1.4 equiv) was added dropwise. After 20 min, i-

Pr₂NEt (0.10 mL, 0.574 mmol, 2.1 equiv) was introduced dropwise.

After 1 h, the reaction mixture was warmed to 0 °C, where it was stirred

for 1 h and then cooled back down to −78 °C. Aldehyde 45 (205 mg,

0.391 mmol, 1.5 equiv) was dissolved in CH₂Cl₂(0.7 mL) and was

added to the boron enolate solution at −78 °C over 15 min via syringe

pump. After 4 h at −78 °C, the reaction mixture was quenched with a 1:1

mixture of MeOH and pH 7 buﬀer (4 mL). While warming to 0 °C, pH 8

buﬀer solution was added to neutralize the reaction mixture to pH 7, and

the biphasic mixture was stirred for 1 h at 0 °C. The layers were

separated, and the aqueous layer was extracted with CH₂Cl₂(3 × 5 mL).

The combined organic layers were dried over MgSO₄, ﬁltered and

concentrated in vacuo. The resulting crude mixture was puriﬁed via ﬂash

chromatography on deactivated SiO₂(2% v/v triethylamine, 7.5%

EtOAc/CH₂Cl₂to 10% EtOAc/CH₂Cl₂) to provide a mixture (ca. 10:1)

of β-hydroxy ketone (+)-46 and corresponding lactone (176 mg, 0.192

mmol, 70%) as a colorless foam: [α]²_D⁰+29.8 (c 0.68 CHCl3); IR (neat)

3417, 2924, 2855, 1719, 1590, 1516, 1461, 1264, 1154 cm⁻¹; ¹H NMR

(500 MHz, CDCl₃) Major δ 6.95−6.91 (m, 3 H), 6.88−6.82 (m, 3 H),

6.49 (s, 1 H), 5.02−4.97 (m, 2 H), 4.95 (s, 2 H), 4.10 (dd, J = 5.3, 10.9

Hz, 1 H), 4.06 (dd, J = 2.9, 9.1 Hz, 1 H), 4.06−4.03 (m, 1 H), 3.94 (d, J =

6.3 Hz, 1 H), 3.89 (s, 3 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.88 (s, 3 H), 3.85

(s, 3 H), 3.72 (s, 3 H), 3.64 (dd, J = 3.7, 7.7 Hz, 1 H), 3.46 (d, J = 5.6 Hz,

1 H), 3.41 (s, 3 H), 3.06 (dd, J = 9.4, 16.0 Hz, 1 H), 2.87 (dd, J = 3.4, 14.3

Hz, 1 H), 2.68 (dq, J = 7.1, 5.4 Hz, 1 H), 2.62 (dd, J = 10.1, 14.1 Hz, 1 H),

2.54 (dd, J = 3.0, 16.4 Hz, 1 H), 2.20 (s, 3 H), 1.96 (ddd, J = 3.9, 6.0, 13.9

Hz, 1 H), 1.58 (ddd, J = 5.0, 7.9, 13.3 Hz, 1 H), 1.21 (d, J = 6.9 Hz, 3 H),

0.96 (s, 3 H), 0.90 (s, 9 H), 0.85 (s, 3 H), 0.04 (s, 3 H), 0.04 (s, 3 H);

Distinct peaks from minor byproduct δ 6.54 (s), 5.16 (dab, J = 12.2 Hz),

5.10 (dab, J = 11.8 Hz), 1.33 (d, J = 7.0 Hz); ¹³C NMR (125 MHz,

CDCl₃) δ 212.5, 171.5, 170.7, 159.0, 155.2, 149.4, 149.3, 149.1, 148.9,

137.1, 129.5, 129.5, 120.0, 119.8, 119.3, 117.9, 111.3, 111.1, 110.8, 110.7,

97.6, 82.3, 77.4, 76.7, 73.0, 71.6, 71.2, 70.6, 70.1, 58.8, 56.1, 56.1, 56.1,

56.1, 53.2, 52.6, 52.1, 42.4, 38.0, 35.8, 30.0, 26.0, 24.9, 18.2, 11.8, 11.4,

−4.3, −4.9; HRMS (ES+) m/z 963.4525 [(M + Na)⁺; calcd for

C₅₀H₇₂O₁₅SiNa 963.4538].

Acid (+)-47. To a solution of β-hydroxy ketone (+)-46 (203 mg,

0.215 mmol) in THF (2.20 mL) and MeOH (0.73 mL) cooled to −78

°C was added a solution of Et₂BOMe (0.31 mL, 1 M in THF, 1.4 equiv).

The reaction mixture was stirred for 25 min before NaBH₄(45 mg,

1.189 mmol, 5.4 equiv) was added. After 5.5 h, the reaction was warmed

to 0 °C and quenched with a 1:1 mixture of MeOH and pH 7 buﬀer (4.0

mL) followed by the addition of m-CPBA (0.330 g, 1.31 mmol, 6.0

equiv) portion-wise. After 30 min, the reaction mixture was warmed to

room temperature, and dimethylsulﬁde was added slowly to quench

remaining peroxides. After 10 min, aq. solution of K₂CO₃(5 mL, 0.1 N)

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

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

washed with brine and then dried over MgSO₄, ﬁltered and concentrated

in vacuo. The crude mixture was puriﬁed via ﬂash chromatography (50%

EtOAc/hexanes to 60% EtOAc/hexanes then ﬂushed with 10% MeOH/

EtOAc) to provide a mixture (ca. 8:1) of diol and lactone (183 mg).

The mixture of diol and lactone was dissolved in MeOH (10.0 mL)

and cooled to 0 °C followed by the addition of H₂O (70 μL, 3.889 mmol,

20.0 equiv) and LiOH (191 mg, 7.975 mmol, 40.0 equiv). The reaction

mixture was allowed to warm to room temperature, and after 35 h, the

reaction mixture was quenched with 50% aqueous acetic acid solution (5

mL). Brine (6 mL) and H₂O (2 mL) were added, and the layers were

separated. The aqueous layer was extracted with EtOAc (5 × 15 mL).

The combined organic layers were dried over MgSO₄, ﬁltered and

concentrated in vacuo. Crude mixture was puriﬁed via column

chromatography on SiO₂(0.1% acetic acid in 60% EtOAc/hexanes to

0.1% acetic acid in 80% EtOAc/hexanes) to provide acid (+)-47 (136

mg, 0.152 mmol, 69% over two steps) as a colorless foam: [α]²_D⁰+22.4 (c

0.9 CHCl₃); IR (neat) 3522, 3058, 2937, 2862, 2862, 1712, 1590, 1515,

1461, 1381, 1261, 1153, 1090 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.33

(d, J = 1.7 Hz, 1 H), 6.92 (m, 3 H), 6.86 (d, J = 8.0 Hz, 1 H), 6.82 (d, J =

8.3 Hz, 1 H), 6.51 (s, 1 H), 5.15 (dab, J = 11.8 Hz, 1 H), 5.09 (dab J =

12.2 Hz, 1 H), 4.99 (s, 2 H), 4.33 (ddd, J = 2.3, 5.5, 8.0 Hz, 1 H) 4.19 (dd,

J = 6.0, 11.7 Hz, 1 H), 4.13 (m, 1 H), 3.91 (s, 3 H), 3.89 (s, 3 H), 3.88 (s,

3 H), 3.86 (s, 3 H), 3.85 (d, J = 4.1 Hz, 1 H), 3.60 (d, J = 12.3 Hz, 1 H),

3.57 (dd, J = 4.0, 7.6 Hz, 1 H) 3.41 (s, 3 H), 3.02 (dd, J = 2.7, 17.2 Hz, 1

H), 2.88 (dd, J = 12.3, 16.4 Hz, 1 H), 2.11 (s, 3 H), 2.08 (m, 1 H), 2.01−

1.93 (m, 2 H), 1.66 (ddd, J = 5.1, 8.0, 13.6 Hz, 1 H), 1.56 (app d, J = 14

Hz, 1 H), 1.07 (d, J = 6.9 Hz, 3 H), 0.94 (s, 3 H), 0.89 (s, 9 H), 0.87 (s, 3

H), 0.05 (s, 3 H), 0.04 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 172.3,

164.4, 161.4, 160.4, 149.5, 149.4, 149.2, 148.7, 142.2, 129.6, 128.9, 120.2,

119.0, 116.3, 111.3, 111.0, 110.9, 110.7, 107.7, 97.9, 82.0, 81.8, 79.0,

72.6, 71.6, 71.1, 70.5, 69.8, 58.7, 56.2, 56.1, 41.5, 38.7, 33.1, 30.6, 29.4,

26.0, 25.0, 18.2, 11.3, 9.5, −4..2, −4.8; HRMS (ES+) m/z 919.4287 [(M

+ Na)⁺; calcd for C₄₈H₆₈O₁₄SiNa 919.4276].

SEM-Ether (+)-48. A solution of acid (+)-47 (116 mg, 0.129 mmol)

in freshly distilled acetone (6.6 mL) was cooled to 0 °C followed by the

dropwise addition of i-Pr₂NEt (0.05 mL, 0.287 mmol, 2.2 equiv) and a

solution of isobutylchloroformate (0.50 mL, 0.64 M in acetone, 2.4

equiv). After 1 h, a solution of NaN₃(0.85 mL, 0.78 M in H₂O, 5 equiv)

was added to the reaction mixture dropwise. After an additional 20 min

at 0 °C, the reaction mixture was diluted with cold H₂O (15 mL). The

layers were separated, and the aqueous layer was extracted with cold

EtOAc (3 × 10 mL). The combined organic layers were dried over

MgSO₄, ﬁltered and concentrated in vacuo. The crude acyl azide was

azeotroped (benzene × 3) and placed under a high vacuum (∼0.1

mmHg) for 30 min. The acyl azide was dissolved in toluene (6.6 mL)

and reaction ﬂask was ﬁtted with a reﬂux condenser and heated to 80 °C.

After 45 min, 2-TMS-ethanol (0.67 mL, 4.674 mmol, 36.2 equiv) was

added via syringe through the top of the condenser. After 5 h at 80 °C,

the reaction mixture was cooled to room temperature and concentrated

in vacuo. The crude mixture was puriﬁed via ﬂash chromatography (40%

EtOAc/hexanes to 50% EtOAc/hexanes) to provide N,O-aminal (+)-71

(90 mg, 0.087 mmol, 67%) as a colorless foam: [α]²_D⁰+3.7 (c 0.5,

CHCl₃); IR (neat) 3502, 3340, 2947, 2859, 1713, 1589, 1515, 1462,

1253, 1151, 1078, 1034, 840 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.34

(d, J = 1.8 Hz, 1 H), 6.93 (m, 3 H), 6.87 (d, J = 8.0 Hz, 1 H), 6.82 (d, J =

8.3 Hz, 1 H), 6.52 (s, 1 H), 5.38, (d, J = 8.8 Hz, 1 H), 5.16 (dab, J = 12.0,

P

dx.doi.org/10.1021/jo400260m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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1

1 H), 5.09 (dab, J = 11.9 Hz, 1 H), 4.99 (s, 2H), 4.89 (d, J = 9.6 Hz, 1 H),

4.31 (ddd, J = 2.2, 6.6, 10.5 Hz, 1 H), 4.19 (ddd, J = 8.3, 10.3, 18.2 Hz, 1

H), 4.12 (m 2 H), 3.98 (d, J = 9.1 Hz, 1 H), 3.92 (s, 3 H), 3.89 (s, 3 H),

3.88 (s, 3 H), 3.87 (m, 1 H), 3.86 (s, 3 H), 3.66 (s, 1 H), 3.62 (d, J = 11.5

Hz, 1 H), 3.56 (m, 1 H), 3.35 (s, 3 H), 3.10 (app d, J = 16.5 Hz, 1 H),

2.83 (dd, J = 12.1, 16.0 Hz, 1 H), 2.37 (m, 1 H), 2.12 (s, 3 H), 1.85 (m, 2

H), 1.45−1.41 (m, 2 H), 1.11 (d, J = 6.9 Hz, 3 H), 0.10 (s, 3 H), 0.97 (t, J

= 8.6 Hz, 2 H), 0.89 (s, 9 H), 0.87 (s, 3 H), 0.04 (s, 3 H), 0.03 (s, 3 H),

0.01 (s, 9 H); ¹³C NMR (125 MHz, CDCl3) δ 163.7, 161.2, 160.3,

157.1, 149.6, 149.4, 149.2, 148.7, 142.2, 129.7, 129.0, 120.1, 119.0, 116.2,

111.3, 111.0, 110.9, 110.8, 108.2, 97.9, 83.7, 83.6, 79.3, 77.4, 73.0, 72.7,

71.1, 70.5, 63.7, 56.2, 56.1, 56.1, 55.8, 43.4, 38.0, 32.9, 31.1, 29.7, 26.1,

26.0, 18.1, 17.8, 11.4, 10.1, −1.3, −4.4, −4.8. HRMS (ES+) m/z

1034.5088 [(M + Na)+; calcd for C₅₃H₈₁NO₁₄Si₂Na 1034.5093].

A solution of N,O-aminal (+)-71 (86 mg, 0.085 mmol) in THF (0.6

mL) was cooled to 0 °C followed by the addition of i-Pr₂NEt (0.13 mL,

0.746 mmol, 9 equiv), SEMCl (0.09 mL, 0.509 mmol, 6 equiv), and

TBAI (8 mg, 0.022 mmol, 0.2 equiv). The reaction mixture was stirred at

0 °C for 15 min and was allowed to warm to room temperature and

stirred for 23 h. The reaction mixture was quenched with a saturated aq.

solution of NaHCO₃(1 mL). The aqueous layer was extracted with

EtOAc (3 × 3 mL). The combined organic layers were dried over

MgSO₄, ﬁltered and concentrated in vacuo. The crude mixture was

puriﬁed via ﬂash chromatography on SiO₂(35% EtOAc/hexanes to 40%

EtOAc/hexanes) to provide SEM ether (+)-48 (0.080 g, 0.070 mmol,

82%) as a colorless foam: [α]²_D⁰+31.6 (c 0.8, CHCl3); IR (neat) 3336,

2952, 2929, 2858, 1716, 1593, 1518, 1464, 1264, 1249, 1160, 1078,

1027, 836 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.33 (d, J = 1.8 Hz, 1

H), 6.98−6.93 (m, 3 H), 6.88 (d, J = 8.7 Hz, 1 H), 6.83 (d, J = 8.3 Hz, 1

H), 6.54 (s, 1 H), 5.60 (bd, J = 9.2 Hz, 1 H), 5.19 (dab, J = 11.7 Hz, 1 H),

5.10 (dab, J = 11.6 Hz, 1 H), 4.98 (s, 2 H), 4.81 (bd, J = 7.9 Hz, 1 H),

4.69−4.59 (m, 2 H), 4.26 (ddd, J = 2.3, 8.4, 11.4 Hz, 1 H), 4.17 (dd, J =

7.5, 10.5 Hz, 1 H), 4.10 (m, 1 H), 3.98−3.94 (m, 2 H), 3.94 (s, 3 H), 3.93

(s, 3 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.58 (dd, J = 4.2 Hz, 1 H), 3.54

−3.48 (m, 1 H), 3.44−3.39 (m, 1 H), 3.36 (s, 3 H), 3.34−3.27 (m, 2 H),

2.65 (dd, J = 7.8, 16.0 Hz, 1 H), 2.47 (m, 1 H), 2.15 (s, 3 H), 2.04 (m, 1

H), 1.82 (ddd, J = 2.4, 9.5, 12.9 Hz, 1 H), 1.66 (m, 1 H), 1.51 (ddd, J =

3.9, 8.5, 14.2 Hz, 1 H), 1.13 (d, J = 7.1 Hz, 3 H), 0.98 (s, 3 H), 0.94 (m, 2

H), 0.90 (s, 9 H), 0.87 (s, 3 H), 0.85−0.77 (m, 1 H), 0.71−0.65 (m, 1

H), 0.05 (s, 3 H), 0.04 (s, 3 H), 0.004 (s, 9 H), −0.13 (s, 9 H) ; ¹³C NMR

(125 MHz, CDCl₃) δ 163.6, 161.3, 160.4, 157.2, 149.6, 149.5, 149.3,

148.8, 142.2, 129.7, 129.0, 120.2, 119.2, 116.3, 111.4, 111.2, 111.0, 110.9,

108.3, 98.0, 93.6, 84.4, 79.4, 77.4, 75.0, 73.5, 71.2, 70.5, 67.6, 65.7, 63.6,

56.3, 56.2, 56.2, 56.1, 56.0, 39.3, 37.7, 31.7, 29.9, 29.3, 26.3, 26.0, 18.2,

18.1, 17.9, 11.4, 9.9, −1.3, −1.4, −4.3, −4.8. high resolution mass

spectrum (ES+) m/z 1164.5879 [(M + Na)⁺; calcd for

C₅₉H₉₅NO₁₅Si₃Na 1164.5907].

Amide (+)-50. To a solution of carboxylic acid (−)-3 (31 mg, 0.102

mmol) in CH₂Cl₂was added a solution of pyridine (0.66 mL, 0.62 M in

CH₂Cl₂, 4 equiv) and a solution of thionyl chloride (0.64 mL, 0.48 M in

CH₂Cl₂, 3 equiv), and the mixture was stirred at rt for 2 h. The resulting

solution was concentrated under a stream of positive N₂and then placed

under a vacuum (∼0.1 mmHg). The crude mixture was dissolved in

toluene (0.4 mL) and transferred to an oven-dried vial via cannula

transfer (ﬂask rinsed with 2 × 0.4 mL toluene). Crude acid chloride 49

was concentrated in vacuo, dissolved in THF (1.0 mL, 0.1 M), and used

in the next step without further puriﬁcation. A solution of carbamate

(+)-48 (0.030 mg, 0.026 mmol) in THF (0.65 mL) was cooled to −78

°C, and a solution of i-PrMgCl (55 uL, 2.0 M in THF, 4 equiv) was

added over 2 min. The yellow solution was stirred for 30 min at −78 °C,

and then a solution of acid chloride 49 (1.0 mL, 0.1 M in THF, 3.9

equiv) was added dropwise over 20 min. After 2.5 h, the reaction mixture

was quenched with a saturated aq. solution of NaHCO₃(1.5 mL) and

warmed to rt. The aqueous layer was extracted with EtOAc (3 × 2 mL),

and the combined organic layers were washed with brine and then dried

over MgSO₄, ﬁltered and concentrated in vacuo. The crude mixture was

puriﬁed via ﬂash chromatography on deactivated silica gel (1% v/v

triethylamine, 25−30% EtOAc/hexanes) to furnish amide (+)-50 (27

mg, 0.019 mmol, 72%) as a white foam: [α]²_D⁰+27.0 (c 0.3, CHCl3); IR

(neat) 2928, 2856, 1716, 1593, 1518, 1464, 1250, 1160, 1083, 1029, 859,

837 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.34 (d, J = 1.9 Hz, 1 H),

6.97−6.93 (m, 3 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.83 (d, J = 8.2 Hz, 1 H),

6.54 (s, 1 H), 5.62 (d, J = 5.7 Hz, 1 H), 5.17 (d, J = 4.4 Hz, 1 H), 5.16 (d, J

= 12.7 Hz, 1 H), 5.10 (d, J = 11.9 Hz, 1 H), 4.98 (s, 2 H), 4.75 (s, 1 H),

4.73 (s, 1 H), 4.67 (dd, J = 6.4, 12.7 Hz, 2 H), 4.59 (dd, J = 7.1, 25.3 Hz, 2

H), 4.35 (m, 1 H), 4.32 (dd, J = 3.6, 6.8 Hz, 1 H), 4.30−4.25 (m, 2 H),

3.93 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.83 (m, 1 H),

3.64 (m, 1 H), 3.58 (ddd, J = 1.6, 9.8, 13.1 Hz, 2 H), 3.53 (m, 1 H),

3.47−3.38 (m, 2 H), 3.36 (s, 3 H), 3.31 (s, 3 H), 3.24 (dd, J = 1.8, 17.7

Hz, 1 H), 3.20 (m, 1 H), 2.86 (dd, J = 12.4, 15.9 Hz, 1 H), 2.26 (m, 1 H),

2.25 (m, 1 H), 2.21 (s, 3 H), 2.05 (m, 1 H), 1.96 (ddd, J = 4.0, 4.0, 13.7

Hz, 1 H), 1.86 (m, 2 H), 1.73 (s, 3 H), 1.70 (m, 1 H), 1.14 (d, J = 7.6 Hz,

3 H), 1.09 (dd J = 7.1, 9.2 Hz, 2 H), 0.92 (s, 3 H), 0.90 (s, 9 H), 0.86 (s, 3

H), 0.84 (m, 2 H), 0.78 (ddd, J = 5.7, 11.6, 13.6 Hz, 1 H), 0.66 (ddd, J =

5.5, 11.6, 13.6 Hz, 1 H), 0.06 (s, 3 H), 0.05 (s, 3 H), 0.05 (s, 9 H), −0.05

(s, 9 H), −0.15 (s, 9 H) ; ¹³C NMR (125 MHz, CDCl₃) δ 175.2, 163.9,

161.2, 160.4, 154.5, 149.5, 149.4, 149.2, 142.9, 148.7 142.6, 129.7, 129.0,

120.2, 119.1, 116.4, 112.8, 111.2, 111.0, 110.8, 110.7, 108.2, 97.7, 95.1,

94.1, 88.5, 81.1, 79.6, 77.4, 77.0, 75.9, 73.0, 71.2, 70.4, 66.3, 66.0, 65.7,

58.4, 57.0, 56.2, 56.1, 56.1, 56.1, 39.8, 39.1, 38.8, 31.8, 31.1, 29.9, 29.9,

26.1, 24.7, 23.1, 18.2, 18.2, 18.1, 17.7, 11.5, 9.8, −1.3, −1.4, −1.4, −4.1,

−4.8. HRMS (ES+) m/z 1450.7513 [(M + Na)⁺; calcd for

C₇₃H₁₂₁NO₁₉Si₄Na 1450.7508].

Ketone (−)-51. To a solution of amide (+)-50 (7.0 mg, 0.005 mmol)

in THF (0.1 mL) was added a solution of TBAF (15 uL, 1 M in THF, 3.0

equiv). The yellow solution was stirred at rt for 1 h and then warmed to

50 °C. After 19 h, additional TBAF (10 uL, 0.010 mmol, 2.0 equiv) was

added. The reaction mixture was stirred at 50 °C for an additional 23 h

and then cooled to rt, quenched with water and extracted with EtOAc (4

× 0.5 mL). The combined organic layers were dried over MgSO₄,

ﬁltered and concentrated in vacuo. The crude mixture was puriﬁed via

ﬂash chromatography on SiO₂(40% EtOAc/hexanes to 60% EtOAc/

hexanes to 70% EtOAc/hexanes) to furnish alcohol (−)-72 (4.5 mg,

0.004 mmol, 79%) as a colorless oil: [α]²_D⁰−3.2 (c 0.3, CHCl₃); IR

(neat) 3426, 2951, 2835, 1715, 1685, 1593, 1517, 1265, 1248, 1160,

1028 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.32 (d, J = 1.6 Hz, 1 H),

7.25 (d, J = 9.4 Hz, 1 H), 6.97−6.92 (m, 3 H), 6.87 (d, J = 8.8 Hz, 1 H),

6.83 (d, J = 8.0 Hz, 1 H), 6.53 (s, 1 H), 5.16 (dab, J = 11.7 Hz, 1 H), 5.09

(dab, J = 11.8 Hz, 1 H), 5.09 (dd, J = 2.5, 5.6 Hz, 1 H), 4.98 (s, 2 H), 4.83

(d, J = 6.6 Hz, 1 H), 4.77 (s, 1 H), 4.76 (s, 1 H), 4.71 (dab, J = 6.3 Hz, 1

H), 4.70 (dab, J = 6.8 Hz, 1 H), 4.60 (d, J = 7.7 Hz, 1 H), 4.40 (d, J = 2.1

Hz, 1 H), 4.27 (ddd, J = 1.9, 7.8, 11.9 Hz, 1 H), 4.08 (m, 1 H), 3.99 (m, 1

H), 3.93 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.74 (m, 2

H), 3.67 (dd, J = 4.5, 4.5 Hz, 1 H), 3.58 (ddd, J = 6.5, 10.3, 10.3 Hz, 1 H),

3.50−3.43 (m, 2 H), 3.37 (s, 3 H), 3.32 (s, 3 H), 3.27 (dd, J = 2.2, 16.7

Hz, 1 H), 2.65 (dd, J = 12.7, 16.4 Hz, 1 H), 2.46 (m, 1 H), 2.37 (dd, J =

8.5, 14.5 Hz, 1 H), 2.19 (dd, J = 4.7, 14.8 Hz, 1 H), 2.14 (s, 3 H), 2.10

(ddd, J = 2.6, 8.4, 8.4 Hz, 1 H), 2.01 (m, 1 H), 1.81 (ddd, J = 2.54, 9.4,

13.5 Hz, 1 H), 1.73 (m, 1 H), 1.70 (s, 3 H), 1.56 (dd, J =4.7, 9.6 Hz, 1 H),

1.54 (dd, J = 5.0, 9.3 Hz, 1 H), 1.15 (d, J = 6.7 Hz, 3 H), 1.00 (s, 3 H),

0.94 (s, 3 H), 0.91 (m, 2 H), 0.85−0.79 (m, 1 H), 0.71−0.69 (m, 1 H),

0.01 (s, 9 H), −0.13 (s, 9 H); ¹³C NMR (125 MHz, CDCl₃) δ 171.2,

163.9, 161.3, 160.4, 149.5, 149.4, 149.2, 148.7, 142.4, 142.2, 129.6, 128.9,

120.2, 119.2, 116.7, 113.0, 111.2, 111.0, 110.9, 110.7, 108.1, 97.7, 94.8,

94.4, 81.8, 81.4, 79.6, 77.4, 75.5, 72.9, 71.1, 70.5, 68.0, 66.2, 65.6, 58.0,

56.3, 56.2, 56.2, 56.1, 56.1, 39.2, 38.3, 37.3, 30.7, 30.0, 29.9, 29.5, 26.0,

22.9, 19.4, 18.2, 18.1, 11.4, 9.6, −1.2, −1.4; HRMS (ES+) m/z

1192.6072 [(M + Na)⁺; calcd for C₆₁H₉₅NO₁₇Si₂Na 1192.6036].

To a solution of alcohol (−)-72 (3.5 mg, 0.003 mmol) in CH₂Cl₂

(0.05 mL) was added NaHCO₃(4.2 mg, 16.6 equiv). The reaction

mixture was cooled to 0 °C, and Dess−Martin periodinane (6.0 mg,

0.015 mmol, 5.0 equiv) was added, and the resulting mixture was stirred

for 3 h. Reaction was quenched with a saturated aq. solution of NaHCO₃

and extracted with EtOAc (4 × 0.5 mL). The combined organic layers

were dried over MgSO₄, ﬁltered and concentrated in vacuo. The crude

mixture was puriﬁed via ﬂash chromatography on SiO₂(40% EtOAc/

hexanes to 50% EtOAc/hexanes) to furnish ketone (−)-51 (3.0 mg,

0.0026 mmol, 87%) as a colorless oil: [α]²_D⁰−14.5 (c 0.2, CHCl₃); IR

(neat) 3403, 2951, 2928, 2835, 1713, 1687, 1593, 1517, 1463, 1265,

1248, 1159, 1080.9, 1029 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.31 (ap

Q

dx.doi.org/10.1021/jo400260m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

s, 1 H), 7.27 (ap s, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 6.93 (m, 2 H), 6.88 (d,

J = 8.4 Hz, 1 H), 6.83 (d, J = 8.2 Hz, 1 H), 6.55 (s, 1 H), 5.18 (dab, J =

12.0 Hz, 1 H), 5.11 (dab, J = 11.7 Hz, 1 H), 5.09 (d, J = 9.8 Hz, 1 H), 4.98

(s, 2 H), 4.83 (dab, J = 6.4 Hz, 1 H), 4.81 (s, 1 H), 4.79 (s, 1 H), 4.73

(dab, J = 6.6 Hz, 1 H), 4.65 (dab, J = 7.0 Hz, 1 H), 4.61 (dab, J = 7.0 Hz, 1

H), 4.38 (d, J = 2.0 Hz, 1 H), 4.29−4.23 (m, 2 H), 3.99 (m, 1 H), 3.93 (s,

3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.75 (m, 1 H), 3.72 (m, 1

H), 3.56 (ddd, J = 6.4, 10.0, 10.0 Hz, 1 H), 3.51−3.42 (m, 2 H), 3.40 (s, 3

H), 3.35 (aps, 1 H), 3.34 (s, 3 H), 3.21 (d, J = 15.9 Hz, 1 H), 2.68 (dd, J =

12.7, 16.4 Hz, 1 H), 2.60 (dd, J = 11.4, 14.9 Hz, 1 H), 2.38 (dd, J = 8.9,

14.9 Hz, 1 H), 2.27 (dd, J = 3.8, 10.9, 1 H), 2.24 (dd, J = 5.2, 12.3, 1 H),

2.14 (s, 3 H), 2.17 −2.09 (m, 1 H), 1.86−1.75 (m, 2 H), 1.73 (s, 3 H),

1.25 (s, 3 H), 1.16 (d, J = 6.6 Hz, 3 H), 1.01 (s, 3 H), 0.96−0.86 (m, 2 H),

0.82−0.76 (m, 1 H), 0.74−0.68 (m, 1 H), 0.01 (s, 9 H), −0.10 (s, 9 H);

¹³C NMR (125 MHz, CDCl₃) δ 210.8, 171.4, 163.7, 161.4, 160.4, 149.5,

149.4, 149.3, 148.7, 142.2, 141.8, 129.5, 128.8, 120.3, 119.2, 116.1, 113.3,

111.2, 111.0, 110.9, 110.7, 108.0, 97.8, 95.0, 94.8, 81.7, 81.4, 79.8, 79.2,

77.6, 74.6, 72.8, 71.1, 70.5, 66.3, 65.8, 58.1, 56.4, 56.2, 56.2, 56.1, 56.1,

49.6, 39.6, 38.8, 38.3, 30.2, 29.9, 24.8, 23.0, 19.5, 18.2, 18.1, 11.4, 9.7,

−1.2, −1.4; high resolution mass spectrum (ES+) m/z 1190.5880 [(M +

Na)⁺; calcd for C₆₁H₉₃NO₁₇Si₂Na 1190.5880].

(−)-Irciniastatin B (2). To a solution of fully protected irciniastatin

B (−)-51 (5.0 mg, 0.0043 mmol) in CH₂Cl₂(0.05 mL) and H₂O (15

uL) was added a suspension of 2,3-dichloro-5,6-dicyano-1,4-benzoqui-

none (0.1 mL, 0.33 M in CH₂Cl₂, 8 equiv). After 24 h, the reaction

mixture was quenched with a saturated aq. solution of NaHCO₃and

extracted with EtOAc (5 × 0.5 mL). The combined organic layers were

dried over MgSO₄, ﬁltered and concentrated in vacuo. The crude

mixture was puriﬁed via ﬂash chromatography (40% EtOAc/hexanes) to

aﬀord a mixture (1:2) of desired bis-phenol and 3,4-dimethoxybenza-

lehyde, respectively.

(+)-irciniastatin A (1) matched to the synthetic sample from our ﬁrst-

generation approach. Characterization data for (+)-irciniastatin A (1):

¹H NMR (500 MHz, MeOD) δ 6.24 (s, 1 H), 5.39 (d, J = 8.3 Hz, 1 H),

4.74 (s, 1 H), 4.71 (s, 1 H), 4.51−4.47 (ddd, J = 3.0, 5.9, 12.0 Hz, 1 H),

4.35 (d, J = 2.6 Hz, 1 H), 3.94 (m, 2 H), 3.67 (ddd, J = 2.6, 3.5, 9.5 Hz, 1

H), 3.60 (dd, J = 4.4, 10.9 Hz, 1 H), 3.50 (dd, J = 2.0, 10.1 Hz, 1 H), 3.35

(s, 3 H), 3.23 (s, 3 H), 3.13 (dd, J = 3.3, 16.7 Hz, 1 H), 2.86 (dd, J = 12.0,

16.6 Hz, 1 H), 2.35 (dd, J = 9.4, 14.8 Hz, 1 H), 2.11 (m, 1 H), 2.10 (s, 3

H), 2.02 (ddd, J = 2.6, 4.5, 13.4 Hz, 1 H), 1.91 (m, 1 H), 1.86−1.74 (m, 2

H), 1.72 (s, 3 H), 1.68 (ddd, J = 2.1, 3.8, 14.6 Hz, 1 H), 1.10 (d, J = 7.1

Hz, 3 H), 0.97 (s, 3 H), 0.90 (s, 3 H); ¹³C NMR (125 MHz, MeOD)

Observable peaks δ 176.3, 172.5, 163.9, 144.0, 141.2, 115.5, 113.1, 101.6,

82.8, 82.3, 82.1, 79.9, 73.6, 73.3, 72.1, 57.8 56.7, 43.4, 39.9, 38.8, 34.5,

30.6, 29.6, 23.8, 23.0, 14.0, 11.0, 9.3; HRMS (ES+) m/z 632.3033 [(M +

1)⁺; calcd for C₃₁H₄₇NO₁₁Na 632.3047]. Characterization data for epi-

1

C(11)-irciniastatin A (52): H NMR (500 MHz, MeOD) Observable

peaks δ 6.25 (s, 1 H), 5.25 (d, J = 3.6 Hz, 1 H), 4.76 (s, 1 H), 4.73 (s, 1

H), 4.51−4.47 (ddd, J = 3.1, 6.8, 12.2 Hz, 1 H), 4.37 (d, J = 2.8 Hz, 1 H),

4.04 (m, 1 H), 3.97 (dd, J = 4.0, 13.2 Hz, 1 H), 3.78 (dd, J = 3.1, 11.8 Hz,

1 H), 3.73−3.67 (m, 2 H), 3.33 (s, 3 H), 3.17 (dd, J = 3.3, 16.7 Hz, 1 H),

2.83 (dd, J = 11.9, 16.2 Hz, 1 H), 2.35 (dd, J = 9.7, 15.0 Hz, 1 H), 2.12

(dd, J = 3.9, 14.2 Hz, 1 H), 2.09 (s, 3 H), 1.96 (m, 2 H), 1.79 (m, 1 H),

1.73 (s, 3 H), 1.63 (m, 2 H), 1.12 (d, J = 7.0 Hz, 3 H), 1.01 (s, 3 H), 0.93

(s, 3 H); ¹³C NMR (125 MHz, MeOD) Observable peaks δ 176.0, 172.6,

164.7, 163.8, 144.0, 141.2, 115.4, 113.2, 101.5, 101.5, 83.0, 82.5, 73.0,

72.7, 72.0, 57.9, 56.7, 42.8, 39.0, 38.7, 30.9, 29.6, 23.1, 22.8, 21.3, 10.9,

9.7; HRMS (ES+) m/z 632.3029 [(M + 1)⁺; calcd for C₃₁H₄₇NO₁₁Na

632.3047].

ASSOCIATED CONTENT

■

S

* Supporting Information

The mixture was treated with a stock solution of MgBr₂/n-BuSH/

MeNO₂in Et₂O (0.21 mL: 25 equiv MgBr₂, 25 equiv n-BuSH, stock

solution made up of 75.4 mg of MgBr₂, 44 μL of n-BuSH, 82 μL of

MeNO₂and 0.82 mL of Et₂O). After 10 h, the reaction mixture was

diluted with EtOAc, quenched with a saturated aq. solution of NaHCO₃

and extracted with EtOAc (5 × 0.5 mL). The combined organic layers

were dried over MgSO₄, ﬁltered and concentrated in vacuo. The crude

mixture was puriﬁed via ﬂash chromatography with water-washed SiO₂

[50 g of SiO₂washed with H₂O (500 mL), then MeOH (500 mL), then

EtOAc (500 mL), then hexanes (500 mL), and dried under a vacuum

overnight, and then deactivated with 5% v/v triethylamine, 35% EtOAc/

hexanes to 80% EtOAc/hexanes] to aﬀord (−)-irciniastatin B (2) (2.0

mg, 0.0033 mmol, 78% over two steps) as a colorless solid: [α]²_D⁰−28.7

(c 0.2, MeOH) IR (neat) 3356, 2925, 2873, 1710, 1651, 1612, 1510,

¹H and ¹³C spectral data of all compounds. This material is

available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

■

Corresponding Author

*E-mail: smithab@sas.upenn.edu.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

Financial support was provided by the National Institute of

Health (Institute of General Medical Sciences) through Grant

No. CA-19033. We thank Drs. George Furst and Rakesh Kohli

(University of Pennsylvania) for help in obtaining the high

resolution NMR and mass spectral data, respectively. The

authors thank the generous help of Professor G. R. Pettit

1

1461, 1380, 1266, 1174, 1103 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

11.11 (s, 1 H), 7.37 (d, J = 10.4 Hz, 1 H), 6.64 (bs, 1 H), 6.30 (s, 1 H),

5.20 (dd, J = 6.4 Hz, 10.1 Hz, 1 H), 4.82 (s, 1 H), 4.79 (s, 1 H), 4.55

(ddd, J = 4.2, 4.2, 11.8 Hz, 1 H), 4.47 (ap t, J = 2.9 Hz, 1 H), 4.21 (ap q, J

= 6.4 Hz, 1 H), 4.09 (d, J = 8.4 Hz, 1 H), 4.00 (dd, J = 1.8, 11.2 Hz, 1 H),

3.79−3.77 (m, 1 H), 3.77 (bs, 1H), 3.65 (bs, 1 H), 3.39 (s, 3 H), 3.36 (s,

3 H), 2.94−2.83 (m, 2 H), 2.67 (ap d, J = 6.4 Hz, 2 H), 2.36 (dd, J = 9.4,

14.5 Hz, 1 H), 2.14 (dd, J = 3.7, 14.5 Hz, 1 H), 2.04 (s, 3 H), 1.91 (1 H,

m), 1.84 (ddd, J = 10.1, 14.6, 24.8 Hz, 1 H), 1.75 (s, 3 H), 1.59 (ap d, J =

14.0 Hz, 1 H), 1.16 (s, 3 H), 1.11 (d, J = 7.2 Hz, 3 H), 1.10 (s, 3H); ¹³C

NMR (125 MHz, CDCl₃) δ 210.3, 173.2, 170.7, 162.5, 161.3, 142.1,

139.9, 113.5, 113.3, 101.7, 101.5, 83.2, 80.5, 80.5, 80.3, 73.8, 72.7, 72.4,

57.9, 56.6, 49.6, 42.8, 38.8, 37.4, 33.0, 28.3, 22.8, 22.3, 19.4, 10.7, 9.2;

HRMS (ES+) m/z 608.3058 [(M + 1)⁺; calcd for C₃₁H₄₆NO₁₁

608.3071].

(+)-Irciniastatin A (1) and epi-C(11)-Irciniastatin A (52). Neat

(−)-irciniastatin B (2) (1 mg, 1.6 μmol) was treated with a solution of

NaBH₄(0.1 mL, 0.024 M in MeOH, 1.5 equiv) at 0 °C. After 15 min, the

reaction mixture was quenched with a saturated aq. solution of NaHCO₃

(0.4 mL) and extracted with EtOAc (3 × 0.5 mL). The combined

organic layers were dried over MgSO₄, ﬁltered and concentrated in

vacuo. The crude mixture (1:1) of (+)-1 and 52 was puriﬁed via

preparatory TLC (70% EtOAc/hexanes, 250 μm SiO₂plate) to provide

(+)-irciniastatin A (1) (0.3 mg, 0.5 μmol 31%) and epi-C(11)-

irciniastatin A (52) (0.3 mg, 0.5 μmol, 31%). All spectral data of

(Arizona State University) for providing the H and ¹³C NMR

1

spectra for (−)-irciniastatin B.

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dx.doi.org/10.1021/jo400260m | J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Total synthesis of (+)-irciniastatin A (a.k.a. psymberin) and (-)-irciniastatin B

DOI: 10.1021/jo400260m

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