Synthetic Access to the Mandelalide Family of Macrolides: Development of an Anion Relay Chemistry Strategy

Article

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

pubs.acs.org/joc

Synthetic Access to the Mandelalide Family of Macrolides:

Development of an Anion Relay Chemistry Strategy

Minh H. Nguyen,^†Masashi Imanishi, Taichi Kurogi, Xuemei Wan, Jane E. Ishmael,

†

‡

Kerry L. McPhail,^‡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

‡

Department of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon 97331, United States

*

S Supporting Information

ABSTRACT: The mandelalides comprise a family of

structurally complex marine macrolides that display signiﬁcant

cytotoxicity against several human cancer cell lines. Presented

here is a full account on the development of an Anion Relay

Chemistry (ARC) strategy for the total synthesis of

(

−)-mandelalides A and L, the two most potent members of

the mandelalide family. The design and implementation of a

three-component type II ARC/cross-coupling protocol and a

four-component type I ARC union permits rapid access

respectively to the key tetrahydrofuran and tetrahydropyran

structural motifs of these natural products. Other highlights of the synthesis include an osmium-catalyzed oxidative cyclization of

an allylic 1,3-diol, a mild Yamaguchi esteriﬁcation to unite the northern and southern hemispheres, and a late-stage Heck

macrocyclization. Synthetic mandelalides A and L displayed potent cytotoxicity against human HeLa cervical cancer cells (EC ,

5

0

1

.3 and 3.1 nM, respectively). This synthetic approach also provides access to several highly potent non-natural mandelalide

analogs, including a biotin-tagged mandelalide probe for future biological investigation.

INTRODUCTION

Scheme 1. Through-Space Type I and Type II ARC Tactics

■

The development of eﬃcient fragment union tactics has been a

hallmark of complex molecule synthesis. One such tactic, Anion

Relay Chemistry (ARC), constitutes a powerful synthetic

strategy that unites multiple components, in a single ﬂask, to

rapidly construct stereodeﬁned, architecturally complex syn-

1

thetic targets. In a broad sense, Anion Relay Chemistry

provides synthetic chemists the ability to control, in a useful

fashion, the ﬂow and reactivity of an anionic site within a

growing molecule. This tactic emanated from a three-

component union protocol exploiting Brook rearrangements,

introduced by our laboratory for the preparation on gram scale

Marine invertebrates, such as tunicates and sponges,

represent an important source of novel bioactive secondary

metabolites, many of which have been developed into

prescription drugs, pharmaceutical lead compounds, and

2

3

spongistatin 1 and discodermolide. The ARC tactic has now

been extensively studied and expanded into two diﬀerent types

4

of through-space negative charge migration (Scheme 1). The

8

utility of each of these multicomponent processes has been

molecular probes for the study of disease mechanisms. Recent

demonstrated in the eﬃcient construction of diverse polyketide

additions to this impressive collection of natural products are

the mandelalide family of macrolides, isolated by McPhail and

co-workers from the South African ascidian Lissoclinum species.

Mandelalides A−D (1−4, Figure 1) were reported in 2012, and

their structures were proposed based on extensive NMR, mass

5

and alkaloid natural produts as well as diversity-oriented

6

libraries comprising “natural product-like” compounds. The

development and application of ARC for eﬀective construction

of structurally complex molecules possessing signiﬁcant

biomedical properties remain a primary goal of our laboratory.

Toward this end, we report here the design and implementa-

tion of an eﬀective synthetic strategy employing both Type I

and II ARC tactics to access members of the highly cytotoxic

9

spectrometric, and GC-MS studies. This series of natural

products comprises an unusual polyketide scaﬀold that is

Received: January 29, 2018

7

mandelalide class of marine natural products.

©

XXXX American Chemical Society

A

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Figure 1. Proposed structures of mandelalides A−D (1−4).

characterized by a trisubstituted tetrahydrofuran moiety, a

glycosylated trisubstituted tetrahydropyran ring, and a con-

jugated diene encased in a 24-membered macrolide framework.

In addition to the intriguing architectural features, mandelalides

A and B were reported by McPhail and co-workers to exhibit

potent low nanomolar cytotoxicity against human NCI-H460

lung cancer cells (IC , 12 and 44 nM, respectively), thus

5

0

rendering the mandelalides and analogs thereof attractive as

lead structures for cancer chemotherapeutics. The minute

quantities of the isolated material and the inaccessibility of the

source organism however have hindered their structural and

biological investigation.

Not surprisingly, the mandelalides attracted considerable

̈

interest from the synthetic community. In 2014, the Furstner

group reported the ﬁrst synthetic work toward this family of

Figure 2. Revised structures of mandelalides A−D (5−8) and new

mandelalides E−L (9−16).

cytotoxic macrolides in which they constructed the originally

10a

reported structure of (−)-mandelalide A (1). By comparing

the spectral data of the natural product with those of the

̈

material obtained through synthesis, Furstner revealed a

mandelalides are eﬀective site-speciﬁc inhibitors of mitochon-

drial function in living cells, and that cells with an oxidative

phenotype are most sensitive to mandelalide-induced decreases

in cell proliferation and viability. Notably, the synthetic work

structural misassignment in the originally proposed structure

of 1. The Ye group later disclosed a reassignment of the

structure of (−)-mandelalide A by total synthesis (5, Figure 2),

wherein all ﬁve stereocenters in the northern hemisphere

7

10,11,13

1

required inversion. Subsequently, Fu

̈

rstner conﬁrmed this

from our laboratory and others

has illustrated the

revision by total synthesis of 5, and in turn predicted similar

indispensable role of organic synthesis in natural products

chemistry for proof of structure and to supply material for

biological investigation. Herein we record a full account of our

synthetic venture that exploits Anion Relay Chemistry to access

the A-type members of the mandelalide family, comprising

(−)-mandelalides A and L (5 and 16), the two most potent

members of the family. Several non-natural mandelalide

analogs, including a mandelalide probe with a biotinolide tag,

were also constructed via this synthetic route to enable future

biological studies.

10b,12

revisions for mandelalides B−D (6−8, Figure 2).

Total

syntheses of the revised structure of (−)-mandelalide A (5)

13

have also been reported by several research groups, including

7

our laboratory.

Interestingly, inconsistent results for the cytotoxic eﬃcacy of

synthetic (−)-mandelalide A (5) were reported by several

investigators, noting weak or disappointing biological activity

10b,11,13

against a small panel of cancer cell lines.

Subsequently,

recollection of the rare tunicate source by McPhail and co-

workers (2013) led to additional natural congeners, man-

delalides E−L (9−16, Figure 2) that facilitated further

RESULTS AND DISCUSSION

Retrosynthetic Analysis. Immediately after we initiated a

synthetic program targeting the originally proposed structure of

■

14

evaluation of the bioactivity of the mandelalide family. The

newly characterized members of the mandelalide family were

classiﬁed into three diﬀerent structural types (Types A−C,

Figure 2), based on three diﬀerent macrocyclic motifs

associated with the prototype structures of mandelalides A−

C. Biological evaluation of the isolated natural products

together with the synthetic material supplied by our laboratory

has yielded important insights into the mechanism of action

and structure−activity relationship of the mandelalides and, in

addition, has provided an explanation for the reported disparity

̈

mandelalide A (1, Figure 1), Furstner reported the synthesis of

1 and suggested the structural misassignment of mandelalide A.

Noting the similarity in structure between 1 and madeirolides A

and B, two marine macrolides isolated from a lithistid

16,17

Leiodermatium sponge (17 and 18, Figure 3),

we decided

to target structure 5, in which the relative conﬁgurations of the

ﬁve stereocenters in the northern hemisphere were inverted, as

the most likely structure of mandelalide A. Indeed, our working

structure for (−)-mandelalide A was later validated by Ye and

15

with respect to biological testing of synthetic mandelalide A.

Results from that study demonstrated that the glycosylated

11

co-workers.

B

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

preparation of epoxide linchpin (−)-25, which was readily

obtained in multigram quantity via a Rh-catalyzed silylformy-

1

9

20

lation of propyne, followed by epoxide formation and then

21

Jacobsen hydrolytic kinetic resolution (Scheme 3A). Selective

Scheme 3. Synthesis of Linchpin 25 (A) and Application in

Type II ARC/Pd Cross-Coupling (B)

Figure 3. Similarity in structure between Mandelalide A and

Madeirolides A and B.

From the retrosynthetic perspective, we envisioned con-

struction of (−)-mandelalide A (5) from three subunits of

comparable complexity for maximal convergency (19−21,

Scheme 2). The macrocyclic aglycon of 5 would arise from

advanced fragments 19 and 20, which would be united via

intermolecular esteriﬁcation followed by a ring-closing Heck

cross-coupling reaction tactic. Final glycosylation with the

known L-rhamnose-derived thioglycosyl donor (+)-21 would

then yield the natural product. The tetrahydrofuran and

tetrahydropyran rings embedded in the northern and southern

hemispheres in turn would be derived from advanced

intermediates 22 and 23, respectively. Importantly, Anion

Relay Chemistry was envisioned to provide access to these key

fragments with great stereochemical ﬂexibility for analog

development and, if needed, structural elucidation of the

natural product. First, fragment 22 would emerge from a Type

II ARC/cross-coupling tactic employing 2-lithio-1,3-dithiane

nucleophilic attack of (−)-25 with 2-lithio-1,3-dithiane (24) at

the least hindered site next generated alkoxide 30 (Scheme 3B).

In the same ﬂask, addition of CuI and HMPA triggered a 1,4-

11

2

Brook rearrangement to form what we envisioned to be an sp -

hybridized carbon nucleophile 31, which readily underwent Pd-

catalyzed cross-coupling reaction with the cis-alkenyl iodide

13b

(+)-26 to furnish the desired tricomponent adduct (+)-22 in

81% yield. This sequence is particularly signiﬁcant, as it

represents the ﬁrst successful example of an ARC/Pd-catalyzed

cross-coupling tactic in complex molecule synthesis.

Adduct (+)-22 was then subjected to what we anticipated

22

would be a chemoselective Jacobsen asymmetric epoxidation,

(

24), bifunctional linchpin 25, and cis-alkenyl iodide 26. A type

with the anticipation that the disubstituted Z-oleﬁn would react

selectively; subsequent alcohol deprotection and epoxide

opening would then deliver 33, possessing the furan ring

system (Scheme 4). This approach, however, proved

unproductive, as diene (+)-22 quickly decomposed under the

epoxidation condition. Attempts to force the ﬁve-member ring

formation via selenoetheriﬁcation also proved unsuccessful.

After this initial setback to construct the furan ring system,

we decided to revise our synthetic strategy (Scheme 5). To this

end, application of the Type II ARC/Pd cross-coupling tactic to

access (−)-37 employing lithiated dithiane 24, epoxide linchpin

(−)-25, and now the trans-alkenyl iodide (+)-36 furnished the

I ARC reaction employing TBS dithiane 27 and epoxides 28

and 29 would give rise to fragment 23. Given our recent

integration of Anion Relay Chemistry with transition-metal-

mediated transformations, we reasoned that this synthetic

venture could provide an excellent opportunity to showcase a

ﬁrst-time Type II ARC tactic in complex molecule synthesis, in

which a negative charge is migrated to an sp -hybridized carbon

center capable of undergoing a cross-coupling reaction with an

electrophilic coupling partner.

18

23

2

Construction of the Northern Hemisphere. Synthesis of

the mandelalide A northern hemisphere (19) began with the

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

C

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Scheme 4. Initial Strategy for Constructing the Furan Ring

Scheme 6. Attempts at Selective Hydrogenation of

Conjugated Diene

hydrogenation conditions, on the other hand, led to undesired

hydrogenation of the disubstituted oleﬁn.

A third possible solution to the now recognized diﬃcult

cyclization would be to translocate the two double bonds in

(+)-38 to out-of-conjugation (Scheme 7). This approach

Scheme 5. Revised Strategy for Constructing the Furan Ring

System

Scheme 7. Structural Modiﬁcation of Linchpin

tricomponent adduct in good yield (81%). Adduct (−)-37 in

turn was subjected to alcohol deprotection, dithiane removal,

and carbonyl reduction to provide diol (+)-38 in 76% yield

over the three steps.

We now envisioned exploiting the 1,3-diol to chelate to a

metal catalyst, facilitating a selective, syn-speciﬁc oxidative

cyclization on the disubstituted oleﬁn of the diene system to

generate 2,5-cis-dihydrofuran 41, possessing the requisite

hydroxyl group at C . A series of catalytic systems employing

2

1

2

4

25

26

osmium, ruthenium, and chromium that were previously

reported to mediate oxidative cyclization of 1,2-diols onto

adjacent alkenes to generate cis-tetrahydrofurans were screened.

All attempts, however, proved unsuccessful, leading either to

decomposition or to very sluggish reactions despite the use of

excess metal catalysts. Several factors presumably hinder the

oxidative cyclization of diol (+)-38, including (a) the less

favorable chelate ring size of the 1,3-diol, compared to the 1,2-

diol systems reported in the literature; (b) the presence of an

acetonide functional group that is incompatible with the acidic

conditions often required for oxidative cyclizations; and (c) the

susceptibility of the allylic alcohol to undergo undesired side

reactions (e.g., oxidation, racemization). The major reason

however for this unproductive transformation, we reason, could

be attributed to the inherent planar conformation of the

conjugated diene system, which inhibits formation of the

requisite transition state 40.

demands a structural modiﬁcation of the tricomponent adduct

(

−)-37, which, given the great ﬂexibility of the ARC protocol,

pleasingly only required a simple modiﬁcation of the epoxide

28

linchpin (−)-25. To test this hypothesis, known epoxide 47a

Scheme 8A) possessing a terminal oleﬁn was synthesized from

(

Scheme 8. Synthesis of Epoxide Linchpin 47 and Revision of

the ARC Tactic

One possible solution to the above problem would be to

selectively hydrogenate the trisubstituted alkene of the

conjugated diene, potentially by exploiting the adjacent

hydroxyl group as a directing group. Alcohol 38 and several

related substrates (42−44, Scheme 6) were each subjected to

hydrogenation conditions employing several asymmetric

27

ruthenium or rhodium catalysts that are known to facilitate

selective hydrogenation of alkenes under the inﬂuence of

directing groups. All attempts toward this approach, however,

also proved unproductive as the conjugated diene system

remained inert to the mild conditions employed. Forcing

D

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

2

9

34

commercially available aldehyde 47b via treatment with

preparation of known epoxide (+)-28 (Scheme 10A), which

2

0

chloromethyl lithium and then subjected to Jacobsen

was readily obtained in multigram quantities from known

2

1

hydrolytic kinetic resolution

to furnish the desired

enantiomer (−)-47. Importantly, the diol byproduct (47c)

from the Jacobsen resolution could also be readily converted to

the desired epoxide (−)-47 in 65% yield via a three-step

reaction sequence. Pleasingly, application of the Type II ARC/

cross-coupling tactic now employing 1,3-dithiane, linchpin

Scheme 10. Synthesis of Epoxide 28 (A) and Application of

Three-Component Type I ARC (B)

(

−)-47, and trans-alkenyl iodide (+)-36 yielded tricomponent

adduct (+)-50 in 89% yield on gram scale, exploiting an

unprecedented CuCN-mediated cross-coupling reaction

3

0

(

Scheme 8B). Signiﬁcantly, attempts to use palladium

catalysis to carry out the same ARC/cross-coupling protocol

failed to provide the desired adduct, demonstrating the unique

utility of this CuCN-mediated cross-coupling reaction in a

multicomponent union protocol (e.g., ARC). Studies to explore

the generality of this reaction are ongoing in our laboratory.

Adduct (+)-50 was then subjected to dithiane removal and

carbonyl reduction to provide 1,3-diol (+)-51 (Scheme 9), now

Scheme 9. Completion of the Northern Hemisphere

35

alcohol (+)-28b via m-CPBA epoxidation of the correspond-

ing trityl ether, followed by Jacobsen hydrolytic kinetic

21

resolution. The diol byproduct 28c could also be readily

converted to the desired epoxide (+)-28 in 73% yield via a

three-step reaction sequence. Nucleophilic attack of (+)-28

with 2-lithio-2-TBS-1,3-dithiane (27; Scheme 10B), followed

by a HMPA-triggered Brook rearrangement, then generated

what we envision to be a carbon nucleophile at the 2-position

of the dithiane (56), which in turn was trapped in the same

36

ﬂask with epoxide (+)-29 to furnish the desired tricomponent

adduct (−)-23 in 68% yield.

possessing a skipped diene system which, as proposed,

successfully underwent an osmium-mediated oxidative cycliza-

A signiﬁcant amount of undesired side-product 57 was

generated in this process, presumably due to partial quenching

of the highly basic anion 56 by the allylic proton in epoxide

(+)-29 (Scheme 10B). This problem was circumvented when

we revised the Type I ARC tactic to a four-component process.

As demonstrated in Scheme 11, application of a Type I ARC

strategy employing TBS dithiane 27a, epoxide (+)-28, and

commercially available (S)-epichlorohydrin as the second

electrophile generated chlorohydrin anion 58, which in turn

led to a new electrophilic terminal epoxide (59) upon warming

2

4

tion to provide the desired intermediate (−)-52. The reaction

conditions for this transformation were optimized by screening

solvents, acids, oxidants, temperatures, substrate concentra-

31

tions, and additives. Under the optimal conditions comprising

pyridine N-oxide (PNO) as the reoxidant in combination with

citric acid and Cu(OTf) in a MeCN/pH 6.5 phosphate buﬀer

2

solvent mixture, (+)-51 was converted to (−)-52 in good yield

with excellent stereoselectivity (88% brsm, >15:1 dr). To the

best of our knowledge, this is the ﬁrst reported example of a

transition-metal-mediated oxidative cyclization of an allylic 1,3-

diol, a diﬃcult substrate due to both the unfavorable ring size

for chelation and a variety of possible side reactions.

Compound (−)-52 was then subjected to protection of the

diol with TBSCl, followed by stereoselective hydrogenation

with Wilkinson’s catalyst to install the desired stereocenter at

C₁₈in 81% yield for the two steps.

Scheme 11. Four-Component Type I ARC

Advanced intermediate (−)-53 was then subjected to

selective desilylation of the primary alcohol, Dess-Martin

3

2

periodinane oxidation, and Stork−Zhao oleﬁnation to furnish

(

−)-54 in 74% yield for the three steps. Final selective removal

33

of the acetonide with CeCl -oxalic acid and protection of the

3

primary alcohol as a TBS ether then aﬀorded the desired

northern hemisphere (−)-19.

Construction of the Southern Hemisphere. Synthesis of

the mandelalide A southern hemisphere (20) began with the

E

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

the reaction mixture to room temperature. Addition of

vinylmagnesium bromide and copper iodide to the same ﬂask

completed construction of the requisite advanced homoallylic

alcohol (−)-23, with only a trace amount of the undesired

product 57 detected (i.e., NMR). Pleasingly, this four-

component ARC adduct could be achieved in a single ﬂask in

then provided advanced intermediate (+)-62 in 76% yield over

the three steps. Subsequent oxidation of the primary alcohol led

to the corresponding aldehyde 63. Methylenation of this rather

sensitive aldehyde at ﬁrst proved problematic, as treatment with

methyltriphenylphosphonium bromide and NaHMDS under

standard Wittig conditions led to the desired product in only

low yield with substantial epimerization at C . Attempts to

8

7% yield on half-gram scale, with an estimated ca. 95% average

11

37

yield for each of the three carbon−carbon bond-forming steps.

Treatment of homoallylic alcohol (−)-23 with mesyl

chloride, followed by TBS removal with TBAF, resulted in

tetrahydropyran (−)-60 (Scheme 12). Dithiane removal

improve this transformation with mild and nonbasic protocols

employing transition metal catalysis failed to provide the

desired product. Gratifyingly, this problem could be addressed

by employing the Julia−Kocienski oleﬁnation tactic with known

38

sulfone 64, to furnish the terminal alkene (−)-65 in good

yield, importantly with no loss in stereochemical integrity.

Finally, ester saponiﬁcation with aqueous LiOH provided the

desired southern hemisphere (−)-20.

Scheme 12. Completion of the Southern Hemisphere

Fragment Union and Completion of the Total

Synthesis of (−)-Mandelalide A. Following construction of

the northern and southern hemispheres, the glycosyl donor

(

+)-21 was readily prepared in multigram quantity from

11,39

commercially available L-rhamnose as previously reported.

Having all fragments in hand, attention was directed toward

fragment assembly (Scheme 13). To this end, the northern and

southern hemispheres (−)-19 and (−)-20 were smoothly

40

united via Yamaguchi esteriﬁcation, furnishing (−)-67 in 85%

yield. Under our reaction conditions, the desired product was

readily obtained without isomerization of the enoate double

10

̈

bond, an issue previously observed by both Furstner and

13a

Altmann. Advanced intermediate (−)-67 was then subjected

to macrocyclization employing an intramolecular Heck

41

reaction to provide the PMB-protected aglycon 68 in good

yield. Attempts to remove the PMB protecting group in 68 with

DDQ, however, led to decomposition due to competing

oxidation of the conjugated diene moiety. This complication

was resolved by exploiting the ﬂexibility of our synthetic

strategy. Speciﬁcally, the PMB group was removed prior to

macrocyclization, to furnish alcohol (−)-70 in near quantitative

followed by diastereoselective reduction with NaBH then led

4

to alcohol (+)-61 in 82% yield. Protecting group manipulations

followed by alkene cross-metathesis with methyl acrylate

employing the second generation Hoveyda−Grubbs catalyst

42

yield. Kahne glycosylation employing sulfoxide (+)-21 then

Scheme 13. Fragments Union and Completion of (−)-Mandelalide A Total Synthesis

F

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

provided glycoside (−)-71 in excellent yield as a single

diastereomer. Macrocyclization employing the Heck reaction

and global desilylation with HF/pyridine then completed the

total synthesis of (−)-mandelalide A (5). The synthetic

material displayed spectral properties identical in all respects

Considering the remarkable cytotoxicity of (−)-mandelalide L,

especially the intriguing role of the additional ester side chain

on the biological activity, we decided to synthesize all three

possible congeners to validate the structure of (−)-mandelalide

L and explore their bioactivity.

1

13

to those reported for the natural product (i.e., H and

C

To this end, the same union strategy for the construction of

NMR and HRMS).

(

−)-mandelalide A was employed with the southern hemi-

Total Synthesis of (−)-Mandelalide L and Related

sphere (−)-20, the glycosyl donor (+)-21, and the northern

fragment (−)-72, the latter obtained via selective butyration of

diol (−)-19a, to generate advanced intermediate (−)-73 in 76%

yield (Scheme 14). Macrocyclization employing a similar Heck

reaction on (−)-73 then provided compound 74, which was

subjected directly to global deprotection to furnish 24-O-

butanoylmandelalide A [(−)-75]. To access the other two

congeners, compound 74 was subjected to selective cleavage of

the butanoyl ester side chain with K CO in MeOH to provide

9

Analogs. Following the original report on the discovery of

mandelalides A−D, recollection of the rare tunicate source by

McPhail and co-workers yielded additional natural congeners of

the mandelalide family, including one new member of the A-

1

4,15

Type macrocycle.

This compound, named (−)-mandelalide

L, displays nanomolar cytotoxicity against both human NCI-

H460 lung cancer cells (EC , 9.8 nM) and HeLa cervical

5

0

cancer cells (EC , 2.8 nM). Preliminary structure elucidation,

50

2

3

together with comparison of NMR data between (−)-man-

delalide L and (−)-mandelalide A, revealed an additional

esteriﬁcation at C (Figure 4). The identity of the ester side

43

(

−)-76 with the free hydroxy group at C . Installation of the

24

pentanoyl and octanoyl ester chains, followed by global

desilylation, furnished (−)-78 and (−)-16, respectively. Having

all three congeners in hand, careful comparison of spectral data

obtained from synthetic materials with those of the puriﬁed

natural product unambiguously conﬁrmed the structure of

2

4

(

−)-mandelalide L as 24-O-octanoylmandelalide A [(−)-16].

The cytotoxic potential of the synthetic material was

evaluated against human HeLa cervical cancer cells, relative

to synthetic (−)-mandelalide A, using assay conditions

comparable to those employed in the original bioassay-guided

14

31

drug discovery screen (Table 1; Figure S1 ). Importantly,

synthetic (−)-mandelalide A and synthetic (−)-mandelalide L

(

EC , 1.3 and 3.1 nM, respectively) revealed biological

50

activities that were entirely consistent with the cytotoxicity

observed in earlier testing of the natural products. Synthetic

Figure 4. Proposed structures of mandelalide L.

(

−)-75 and (−)-78 also proved to be fully eﬃcacious

chain, however, was unclear as initial MS proﬁling of the

minute semipure natural product sample suggested three likely

possibilities: a butanoyl, a pentanoyl, or an octanoyl moiety.

cytotoxins with EC50 values of 2.1 and 0.7 nM, respectively.

Seco-mandelalide A methyl ester (−)-80, obtained from 79 as a

43

side product during the ester saponiﬁcation of 74 (Scheme

Scheme 14. Total Synthesis and Structural Validation of (−)-Mandelalide L

G

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Table 1. Cytotoxicity of Synthetic Mandelalide Analogs

Against Human HeLa Cells

employed in detailed biological investigations, in conjunction

with streptavidin aﬃnity-based chromatography, to further

elucidate cellular target(s) of the mandelalides.

compound

5

EC₅₀(nM)

1.3 ± 0.1

SUMMARY

■

16

75

78

80

82

84

3.1 ± 0.4

2.1 ± 0.6

0.7 ± 0.1

inactive at 300 nM

1.5

The evolution of an eﬀective dual Anion Relay Chemistry

strategy for the construction of (−)-mandelalide A has been

achieved. The synthesis was completed with a longest linear

reaction sequence of 16 steps from epoxide 47 in ca. 20%

overall yield. Through rational design of new linchpins and the

strategic selection of coupling partners, the value of both Type I

and Type II ARC tactics has been demonstrated in this

synthetic venture. The northern hemisphere was constructed

via a novel three-component Type II ARC/CuCN-mediated

cross-coupling protocol, while the southern hemisphere was

secured via a highly eﬀective four-component Type I ARC

union, both conducted on preparative scale, employing readily

accessible and/or commercially available building blocks. This

work clearly showcases ARC as a powerful synthetic tactic for

the rapid union of multiple, structurally simple starting

materials in a highly eﬃcient and iterative fashion.

18

1

4), displayed no biological activity against HeLa cells. These

data demonstrate the essential requirement of the macrolactone

moiety for the cytotoxicity of the A-Type mandelalides series.

Moreover, the presence of an additional ester moiety on C₂₄

has no noticeable eﬀect on the biological activity of

(

−)-mandelalide A. This particularly important observation

holds promise for the future determinations of the mandelalide

cellular binding target by functionalization of the 24-OH with a

chemical probe. To this end, two mandelalide analogs

possessing alkyne and biotin probes were prepared, the latter

via attachment of a biotin tether via a Huisgen 1,3-dipolar

cycloaddition to the derived acetylenic ester (−)-82 (Scheme

1

44

Construction of the northern hemisphere also demonstrates

an important advantage of ARC that permits access to a wide

variety of scaﬀolds via ready customization of the coupling

partners with programmable, preloaded functionality and

stereochemistry.

4

5

5). The polyethylene glycol (PEG) unit in turn was employed

Scheme 15. Synthesis of Biotin-Tagged Mandelalide A

In addition to the ﬁrst total synthesis and structural

validation of (−)-mandelalide L, this highly convergent, ﬂexible

synthetic strategy permitted rapid functionalization of man-

delalide A at the 24-OH to access several Type A non-natural

mandelalide analogs that exhibit potent cytotoxicity against

human HeLa cervical cancer cells. Application of the strategies

presented here for the synthesis of other members of

mandelalide family (Types B and C) and biological

investigation employing the derived synthetic material to

elucidate the cellular target of this family of natural products

continue in our laboratories.

EXPERIMENTAL SECTION

Material and Methods. All moisture-sensitive reactions were

performed using syringe-septum cap techniques under an inert

■

atmosphere of N . All glassware was ﬂame-dried or dried in an oven

2

(

140 °C) for at least 4 h prior to use. Reactions were magnetically

stirred unless otherwise stated. Tetrahydrofuran (THF), dichloro-

methane (CH Cl ), diethyl ether (Et O), and toluene were dried by

2

passage through alumina in a Pure Solve PS-400 solvent puriﬁcation

system. THF was degassed vigorously via freeze−pump−thaw before

being employed in Anion Relay Chemistry protocols. Unless otherwise

stated, solvents and reagents were used as received. Analytical thin

layer chromatography was performed on precoated silica gel 60 F-254

plates (particle size 40−55 μm, 230−400 mesh) and visualized by a

UV lamp or by staining with PMA (2 g phosphomolybdic acid

dissolved in 20 mL of absolute ethanol), KMnO (1.5 g of KMnO , 10

as a linker molecule between biotin and mandelalide A to

increase solubility of the overall molecule in water. Pleasingly,

biological testing revealed that attachment of an alkyne tag

4

[

(−)-82] or a biotin fragment to the mandelalide A structure at

g of K CO and 2.5 mL of 5% aq. NaOH in 150 mL of H O), or CAM

2

3

2

C

[(−)-84] does not signi ﬁ cantly aﬀect the cytotoxicity of

(4.8 g of (NH ) Mo O ·4H O and 0.2 g of Ce(SO ) in 100 mL of a

4 6 7 24 2 4 2

24

31

mandelalide A (Table 1; Figure S2A ). Synthetic (−)-82 and

−)-84 displayed nanomolar potency against HeLa cell viability

with an EC₅₀value of 1.5 and 18 nM, respectively. Moreover,

−)-84 retained the ability to inhibit the complex V ATP

synthase activity of isolated bovine heart mitochondria (Figure

3.5 N H SO solution). Column chromatography was performed using

2 4

silica gel (Silacycle Silaﬂash, P60, 40−63 μm particle size, 230−300

mesh) and compressed air pressure with commercial grade solvents.

Yields refer to chromatographically and spectroscopically pure

compounds, unless otherwise stated. NMR spectra were recorded at

(

1

13

5

00 MHz/125 MHz ( H NMR/ C NMR) on a Bruker Avance III

00 MHz spectrometer at 300 K. Chemical shifts are reported relative

3

1

S2B ), providing strong evidence for an interaction between

the biotin-tagged molecule and biological target of mandelalide

A in cell-free assays. Together with the synthetic natural

products, these non-natural analogs are currently being

to chloroform (δ 7.26), acetone (δ 2.05), methanol (δ 3.31), or

1

benzene (δ 7.16) for H NMR and chloroform (δ 77.16), acetone (δ

1

3

1

29.84), methanol (δ 49.00), or benzene (δ 128.06) for C NMR. H

H

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

NMR spectra are tabulated as follows: chemical shift, multiplicity (s =

singlet, d = doublet, t = triplet, q = quartet, qn = quintet, dd = doublet

of doublets, ddd = doublet of doublet of doublets, dddd = doublet of

doublet of doublet of doublets, dt = doublet of triplets, m = multiplet,

b = broad), coupling constant, and integration. ¹³C NMR spectra are

tabulated by observed peak. Optical rotations were measured on a

Jasco P-2000 polarimeter. Melting points were determined using a

Thomas-Hoover capillar melting point apparatus and are uncorrected.

Infrared spectra were measured on a Jasco FT/IR 480 plus

spectrometer. High-resolution mass spectra (HRMS) were obtained

at the University of Pennsylvania on a Waters GCT Premier

spectrometer. GPC analysis of the polymer samples were done on a

PerkinElmer Series 10 high-performance liquid chromatography

mmol), and the resulting mixture was stirred at room temperature

under air for 30 min. The volatile components were removed via

rotary evaporation, and the remaining residue was dissolved in epoxide

25a (2.49 g, 12.55 mmol) and 2 mL of THF. The solution was then

cooled to 0 °C, and H O (160 μL, 8.79 mmol) was added via syringe.

2

The resulting mixture was stirred at room temperature for 8 days, after

which time Et O (50 mL) was added; the mixture was ﬁltered through

2

a short pad of silica gel and concentrated in vacuo. Flash

chromatography on silica gel (5% Et O/Hexanes), followed by

2

Kugelrohr distillation (70−90 °C, 0.025 mmHg), aﬀorded the desired

epoxide 25 as a colorless oil (1.12 g, 5.65 mmol, 45%, >95% ee based

1

20

on H NMR analysis of 37): [α] −33.97 (c 1.04, CH Cl ).

D

2

Compound (−)-47. Chloroiodomethane (7.03 mL, 96.45 mmol)

was added to a stirred solution of aldehyde 47b (4.575 g, 32.15 mmol)

in 100 mL of THF at −78 °C. A solution of n-BuLi (2.5 M, 38.6 mL,

96.45 mmol) in hexanes was added dropwise via syringe over 30 min.

The obtained solution was then stirred at −78 °C for 1 h, then

tetrabutylamonium iodide (TBAI, 1.19 g, 3.22 mmol) was added, and

the solution was then stirred at room temperature for 15 h. The

(

HPLC), equipped with an LC-100 column oven (30 °C), a Nelson

Analytical 900 Series integration data station, a PerkinElmer 785 UV−

vis detector (254 nm), a Varian star 4090 refractive index detector, and

three AM gel columns (500 Å, 5 μm; 1000 Å, 5 μm; and 10 Å, 5 μm).

4

THF (Fisher, HPLC grade) was used as eluent at a ﬂow rate of 1 mL/

min. SFC puriﬁcations were performed with a JASCO system

equipped with a Chiralpak AD-H column (10 mm × 250 mm), a

PU-280-CO2 plus CO2 Delivery System, a CO-2060 plus Intelligent

Column Thermostat, an HC-2068-01 Heater Controller, a BP-2080

plus Automatic Back Pressure Regulator, an MD-2018 plus Photo-

diode Array Detector (200−648 nm), and PU-2080 plus Intelligent

HPLC Pumps.

solution was then quenched with saturated aqueous NH

and deionized H O (50 mL). The resulting mixture was extracted with

Et O (2 × 150 mL). The combined organic layers were washed with

brine, dried with MgSO , and concentrated in vacuo. The crude

product was puriﬁed by ﬂash chromatography on silica gel (2−5%

Et O/Hexanes) to aﬀord the desired epoxide 47a as a pale yellow oil

Cl (50 mL)

4

2

4

2

−1

Preparation of Coupling Partners for Anion Relay Chem-

istry. Compound 25b. A tared, septum-capped, 50 mL vial containing

(4.77 g, 30.54 mmol, 95%): IR (ﬁlm, cm ) 3049, 2955, 1637, 1419,

1249, 1160, 953, 891, 852; H NMR (500 MHz, CDCl ) δ 5.00 (bs,

1

3

2

3

5 mL of MeCN and a stir bar was purged with propyne gas (1.36 g,

4.0 mmol) and weighed to determine the mass of dissolved propyne

1H), 4.75 (bs, 1 H), 3.26 (t, J = 3.0 Hz, 1 H), 2.86 (dd, J = 5.5, 4.2 Hz,

1 H), 2.60 (dd, J = 5.5, 2.6 Hz, 1 H), 1.45 (dd, J = 21.6, 14.1 Hz, 2 H),

0.04 (s, 9 H); ¹³C NMR (125 MHz, CDCl ) δ 143.5, 109.8, 54.3, 48.2,

gas in solution. Liquid tert-butyldimethylsilane (1.9 mL, 11.3 mmol)

was added via syringe, and the resulting solution was solidiﬁed by

cooling down to −78 °C. The septum was removed, solid catalyst

3

+

21.3, −1.26; HRMS (CI ) m/z (M − Me) : calcd for C H OSi,

8

16

156.0970; found, 156.0966.

Rh(acac)(CO) (29.2 mg, 0.113 mmol) was added, and the vial was

To a mixture of the precatalyst (R,R)-(−)-N,N′-bis(3,5-di-tert-

butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) (147 mg, 0.244

mmol) in 1 mL of toluene was added glacial acetic acid (28 μL, 0.487

mmol), and the resulting mixture was stirred at room temperature

under air for 30 min. The volatile components were removed via

rotary evaporation, and the remaining residue was dissolved in epoxide

47a (3.806 g, 24.35 mmol) and 3.4 mL of THF. The solution was then

2

then quickly assembled into a Parr bomb and heated to 90 °C under

an atmosphere of CO (500 psi) for 15 h. The solution was then cooled

to room temperature and carefully removed from the Parr bomb. The

resulting mixture was extracted with Et O (2 × 100 mL). The

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

2

and concentrated in vacuo. The crude product was puriﬁed by ﬂash

chromatography on silica gel (5% Et O/Hexanes) to aﬀord the desired

cooled to 0 °C, and H O (241 μL, 13.39 mmol) was added via syringe.

2

aldehyde 25b as a yellow oil (2.06 g, 11.19 mmol, 99%): IR (ﬁlm,

The resulting mixture was stirred at room temperature for 5 days, after

−1

cm ) 2939, 2854, 2738, 1687, 1594, 1470, 1362, 1323, 1252, 1029,

which time Et O (30 mL) was added; the mixture was ﬁltered through

2

1

008, 841, 782, 705; H NMR (500 MHz, CDCl ) δ 9.82 (s, 1 H),

a short pad of silica gel and concentrated in vacuo. Flash

3

6

.86 (q, J = 1.4 Hz, 1 H), 1.94 (d, J = 1.4 Hz, 3 H), 0.93 (s, 9 H), 0.22

chromatography on silica gel (5% Et O/Pentanes) aﬀorded the

2

(

s, 6 H); ¹³C NMR (125 MHz, CDCl ) δ 193.7, 153.2, 150.4, 26.5,

desired epoxide 47 as a pale yellow oil (1.71 g, 10.96 mmol, 45%,

3

+

20

1

9.2, 17.1, −2.9; HRMS (CI ) m/z (M − Me) : calcd for C H OSi,

>95% ee as determined via SFC analysis of alcohol 48a): [α] −5.12

9

17

D

169.1049; found, 169.1049.

(c 0.083, CH Cl ). Diol 47c (2.08 g, 49%) was also obtained following

2

Compound (−)-25. Chloroiodomethane (2.85 mL, 39.13 mmol)

ﬂash chromatography and could be converted to epoxide (−)-47 in a

three-step reaction sequence: to a solution of 47c (4.28 g, 24.57

mmol) in 100 mL of CH Cl at 0 °C was added pyridine (2.97 mL,

36.86 mmol) and pivaloyl chloride (3.33 mL, 27.03 mmol). The

resulting solution was slowly warmed to room temperature over 15 h.

was added to a stirred solution of aldehyde 25b (2.405 g, 13.04 mmol)

in 35 mL of THF at −78 °C. A solution of n-BuLi (2.43 M, 16.1 mL,

2

3

9.13 mmol) in hexanes was added dropwise via syringe over 15 min.

The obtained solution was then stirred at −78 °C for 1 h, then

tetrabutylammonium iodide (TBAI, 481.7 mg, 1.304 mmol) was

added, and the solution was then stirred at room temperature for 15 h.

The reaction mixture was then diluted with Et O (100 mL) followed

2

by quenching with saturated aqueous NH Cl (50 mL). The resulting

4

The solution was quenched with saturated aqueous NH Cl (50 mL)

mixture was extracted with Et O (2 × 150 mL). The combined organic

4

2

and deionized H O (50 mL). The resulting mixture was extracted with

layers were washed with saturated aqueous NaHCO and brine, dried

2

3

Et O (2 × 100 mL). The combined organic layers were washed with

with Na SO , and concentrated in vacuo. The obtained crude product

2

4

brine, dried with MgSO , and concentrated in vacuo. The crude

was then taken up in 150 mL of CH Cl at 0 °C followed by addition

2 2

4

product was puriﬁed by ﬂash chromatography on silica gel (2−5%

of Et N (8.56 mL, 61.43 mmol), mesyl chloride (3.81 mL, 49.14

3

Et O/Hexanes) to aﬀord the desired epoxide 25a as a yellow oil (2.42

mmol), and a catalytic amount of DMAP (150.3 mg, 1.23 mmol). The

resulting solution was stirred at room temperature for 28 h. The

2

−1

g, 11.2 mmol, 94%): IR (ﬁlm, cm ) 2945, 2854, 1616, 1470, 1380,

250, 895, 841, 761, 686; H NMR (500 MHz, CDCl ) δ 5.64 (bs, 1

1

solution was then quenched with saturated aqueous NH Cl (50 mL).

3

4

H), 3.59 (t, J = 3.2 Hz, 1 H), 2.86 (t, J = 4.8 Hz, 1 H), 2.79 (dd, J =

.2, 2.8 Hz, 1 H), 1.67 (d, J = 1.2 Hz, 3 H), 0.91 (s, 9 H), 0.14 (s, 3

The resulting mixture was extracted with CH Cl (2 × 100 mL). The

2

5

combined organic layers were washed with brine, dried with Na SO ,

2 4

13

H), 0.13 (s, 3 H); C NMR (125 MHz, CDCl ) δ 150.8, 128.9, 53.4,

and concentrated in vacuo. The obtained crude was then directly taken

3

+

4

6.4, 26.5, 20.1, 17.1, −3.6, −3.7; HRMS (ES ) m/z (M + H) : calcd

in 250 mL of MeOH. Solid K CO (7.5 g, 54.1 mmol) was added, and

2

3

for C H OSi, 199.1518; found, 199.1529.

the resulting mixture was stirred for 37 h. The reaction mixture was

11

23

To a mixture of the precatalyst (R,R)-(−)-N,N′-bis(3,5-di-tert-

butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) (379 mg, 0.628

mmol) in 1 mL of toluene was added glacial acetic acid (72 μL, 1.255

then diluted with Et O (200 mL) followed by quenching with brine

2

(100 mL) and deionized H O (100 mL). The resulting mixture was

2

extracted with Et O (2 × 150 mL). The combined organic layers were

2

I

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

washed with brine, dried with Na SO , and concentrated in vacuo.

Compound (+)-28. To a 1 L round-bottomed ﬂask containing

28b1 (13.06 g, 38.1 mmol) and Na HPO (10.8 g, 38.1 mmol) in 380

2

4

Puriﬁcation by ﬂash chromatography on silica gel (5% Et O/Pentanes)

2

4

aﬀorded the desired epoxide 47 as a pale yellow oil (2.50 g, 65% over

the 3 steps).

Compound (−)-48a. A solution of n-BuLi (2.48 M, 508 μL, 1.26

mmol) in hexanes was added to a stirred solution of 1,3-dithiane

mL of CH Cl at 0 °C was added mCPBA (<77% commercial supply,

2 2

12.0 g, ca. 53.5 mmol), and the resulting mixture was stirred at room

temperature for 14 h, after which time TLC indicated complete

consumption of 28b1. The reaction was quenched with saturated

aqueous NaHCO and saturated aqueous Na SO (1:1 mixture, ca.

(

151.5 mg, 1.26 mmol) in 2 mL of THF at −20 °C and stirred for 2 h.

3

2

3

A solution of epoxide 47 (164.1 mg, 1.05 mmol) in 0.5 mL of THF

was added via cannula dropwise (followed with a 0.5 mL rinse with

THF). The resulting solution was stirred at −20 °C for 3 h and then

cooled to −78 °C, and HMPA (183 μL, 1.05 mmol) was then added.

The resulting mixture was warmed to −40 °C and stirred for another 2

h. The solution was then cooled to −78 °C, and aqueous H SO (1 N,

300 mL) at 0 °C. The resulting mixture was extracted with CH Cl

2 2

three times, and the combined organic extracts were washed with

saturated aqueous NaHCO , dried over anhydrous sodium sulfate, and

3

ﬁltered. The organic solvents were removed under reduced pressure to

give crude material, which was puriﬁed by silica gel column

chromatography (10% Et O/Hexanes) to aﬀord epoxide 28a as a

2

4

2

mL) was added dropwise. The resulting mixture was warmed to

colorless oil (12.6 g, 35.1 mmol, 92%, 1:1 mixture of diaster-

−1

room temperature and extracted with Et O (3 × 50 mL). The

combined organic layers were washed with saturated aqueous

eoisomers): IR (ﬁlm, cm ) 3056, 2917, 1490, 1448, 1219, 1153, 1071,

2

1

899, 764, 746, 707; H NMR (500 MHz, CDCl ) δ 7.44 (d, J = 7.5 Hz,

3

NaHCO , brine, dried with MgSO , and concentrated in vacuo. The

crude product was puriﬁed by ﬂash chromatography on silica gel (20%

6 H), 7.33−7.27 (m, 6 H), 7.25−7.20 (m, 3 H), 3.02−2.94 (m, 2 H),

2.91−2.82 (m, 1 H), 2.72 (t, J = 4.5 Hz, 0.5 H), 2.64 (t, J = 4.5 Hz, 0.5

H), 2.45−2.40 (m, 0.5 H), 2.37−2.33 (m, 0.5 H), 2.06−1.94 (m, 1 H),

3

4

Et O/Hexanes) to aﬀord 48a as a colorless oil (232.3 mg, 0.84 mmol,

2

20

8

(

8

0%, >95% ee via SFC analysis): [α] −7.75 (c 1.13, CH Cl ); IR

ﬁlm, cm ) 3436, 2951, 2898, 1636, 1423, 1276, 1248, 1159, 1053,

86, 853, 692, 668; H NMR (500 MHz, CDCl ) δ 4.98 (s, 1 H), 4.70

1.78−1.67 (m, 1 H), 1.43−1.31 (m, 1 H), 1.06 (d, J = 6.7 Hz, 1.5 H),

D

2

−1

13

1.02 (d, J = 6.7 Hz, 1.5 H); C NMR (125 MHz, CDCl ) δ 144.5,

3

1

144.4, 128.9, 127.9, 127.03, 127.02, 86.4, 68.3, 67.9, 51.5, 50.9, 47.7,

3

+

(

s, 1 H), 4.28−4.22 (m, 2 H), 2.95−2.82 (m, 4 H), 2.17−2.10 (m, 1

47.2, 37.1, 36.9, 32.7, 32.1, 18.1, 17.4; HRMS (ES ) m/z (M + Na) :

H), 2.05−1.97 (m, 1 H), 1.94−1.85 (m, 2 H), 1.81−1.76 (m, 1 H),

calcd for C H O Na, 381.1831; found, 381.1829.

25

26

2

1

.63 (d, J = 14.1 Hz, 1 H), 1.41 (d, J = 13.9 Hz, 1 H), 0.04 (s, 9 H);

To a 50 mL two-necked round-bottomed ﬂask containing

precatalyst (R,R)-(−)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclo-

hexanediaminocobalt(II) (404 mg, 0.669 mmol) in 8.2 mL of toluene

was added glacial acetic acid (76.5 μL, 1.34 mmol), and the mixture

was stirred at room temperature for 1 h. The volatile components were

then removed, and the residue was dried under high vacuum (∼30

min). To the resulting residue was added a solution of epoxide 28a

(12.0 g, 33.5 mmol) in 12 mL of THF, and the resulting mixture was

1

3

C NMR (125 MHz, CDCl ) δ 149.4, 107.6, 72.2, 44.3, 41.7, 30.4,

3

+

3

0.1, 26.1, 22.9, −1.08; HRMS (ES ) m/z (M + H) : calcd for

C H OS Si, 277.1116; found, 277.1110.

12

25

2

Compound (+)-36. To a ﬂask containing CrCl (18.65 g, 151.7

2

mmol) under N were added 140 mL of 1,4-dioxane and 23 mL of

2

THF. The mixture was stirred vigorously for 45 min at room

temperature to obtain a homogeneous suspension. Recrystallized CHI₃

(

19.65 g, 49.91 mmol) was added, and the resulting mixture was

cooled to 0 °C. To the solution was added H O (332 μL, 18.4 mmol),

2

stirred for 2 h at room temperature, at which time a solution of known

aldehyde 36a (3.13 g, 21.7 mmol) in 7 mL of 1,4-dioxane was added

dropwise via cannula. The resulting mixture was stirred for 3 h at room

temperature. The reaction was then quenched with 100 mL of

deionized H O and extracted with Hexanes (3 × 100 mL). The

combined organic layers were washed with saturated aqueous

and the mixture was stirred at room temperature for 3 days, after

1

which H NMR indicated consumption of a diastereoisomer of 28a.

The reaction mixture was puriﬁed by silica gel column chromatog-

raphy (15% Et

O/Hexanes) to aﬀord the epoxide 28 (5.84 g, 16.3

2

1

20

mmol, 49%, >12:1 d.r. as determined by H NMR analysis): [α]

+2.52 (c 0.67, CH Cl ); H NMR (500 MHz, CDCl ) δ 7.44 (d, J =

2

D

1

2

3

Na S O , brine, dried with Na SO , and concentrated in vacuo. The

crude product was puriﬁed by ﬂash chromatography on silica gel (5%

7.5 Hz, 6 H), 7.33−7.27 (m, 6 H), 7.25−7.20 (m, 3 H), 3.02−2.94 (m,

2 H), 2.91−2.86 (m, 1 H), 2.72 (t, J = 4.5 Hz, 1 H), 2.45−2.40 (m, 1

2

3

2

4

Et O/Hexanes) to aﬀord the desired vinyl iodide (+)-36 as a colorless

H), 2.06−1.94 (m, 1 H), 1.78−1.72 (m, 1 H), 1.39−1.31 (m, 1 H),

2

20

13

oil (4.13 g, 15.4 mmol, 71%): [α] +6.45 (c 0.59, CHCl ); IR (ﬁlm,

1.02 (d, J = 6.7 Hz, 3 H); C NMR (125 MHz, CDCl

3

) δ 144.5,

D

3

−

1

cm ) 2984, 2934, 2877, 1607, 1370, 1212, 1153, 1065, 948, 835; H

128.9, 127.8, 127.0, 86.4, 68.3, 50.9, 47.7, 36.9, 32.1, 17.4. Diol 28c

(5.55 g, 44%) was also obtained following ﬂash chromatography and

could be converted to epoxide 28 in a three-step reaction sequence: to

NMR (500 MHz, CDCl ) δ 6.52 (dt, J = 14.5, 7.3 Hz, 1 H), 6.16 (d, J

3

=

14.5 Hz, 1 H), 4.15 (qn, J = 6.2 Hz, 1 H), 4.03 (dd, J = 8.0, 6.0 Hz, 1

H), 3.57 (dd, J = 8.0, 6.8 Hz, 1 H), 2.40−2.25 (m, 2 H), 1.41 (s, 3 H),

a solution of 28c (8.22 g, 21.8 mmol) in 87 mL of CH Cl at 0 °C

2 2

1

6

.35 (s, 3 H); ¹³C NMR (125 MHz, CDCl ) δ 141.5, 109.4, 77.7, 74.4,

were added pyridine (2.64 mL, 32.6 mmol) and pivaloyl chloride (3.22

mL, 26.2 mmol). The resulting solution was slowly warmed to room

temperature over 8 h. The reaction mixture was then diluted with

Et O (100 mL) followed by quenching with saturated aqueous NH Cl

3

+

8.8, 40.2, 27.0, 25.7; HRMS (CI ) m/z (M − Me) : Calcd for

C H O I, 252.9726; found, 252.9715.

7

10

2

Compound (+)-28b1. To a 1 L round-bottomed ﬂask containing

2

4

2

8b (6.12 g, 61.1 mmol) in 190 mL of CH Cl at 0 °C were added

(50 mL). The resulting mixture was extracted with Et O (2 × 150

2

pyridine (12.4 mL, 153 mmol), trityl chloride (34.1 g, 122 mmol), and

DMAP (1.49 g, 12.2 mmol). The resulting solution was stirred at

room temperature for 39 h, after which time TLC indicated complete

mL). The combined organic layers were washed with saturated

aqueous NaHCO and brine, dried with Na SO , and concentrated in

3

2

4

vacuo. The obtained crude product was then taken up in 145 mL of

CH Cl at 0 °C followed by addition of Et N (7.60 mL, 54.5 mmol),

consumption of 28b. The reaction mixture was diluted with CH Cl₂

2

3

and water at 0 °C. The resulting mixture was washed with water twice,

mesyl chloride (3.37 mL, 43.5 mmol), and a catalytic amount of

DMAP (133.2 mg, 1.09 mmol). The resulting solution was stirred at

room temperature for 17 h. The solution was then quenched with

saturated aqueous NH Cl twice, and brine, dried over anhydrous

4

sodium sulfate, and ﬁltered. The organic solvents were removed under

reduced pressure to give a crude residue, which was puriﬁed by silica

gel column chromatography (3% EtOAc/Hexanes) to aﬀord 28b1 as a

saturated aqueous NH Cl (50 mL). The resulting mixture was

4

extracted with CH Cl (2 × 100 mL). The combined organic layers

2

0

colorless oil (14.9 g, 43.5 mmol, 71%): [α] +0.57 (c 0.83, CH Cl );

were washed with brine, dried with Na SO , and concentrated in

D

2

2 4

−1

IR (ﬁlm, cm ) 3061, 2916, 1636, 1491, 1448, 1153, 1072, 913, 744,

vacuo. The obtained crude product was then directly taken in 220 mL

1

7

05; H NMR (500 MHz, CDCl ) δ 7.45 (d, J = 7.5 Hz, 6 H), 7.32−

of MeOH. Solid K CO (6.63 g, 48.0 mmol) was added, and the

3

2

3

.27 (m, 6 H), 7.25−7.21 (m, 3 H), 5.75−5.65 (m, 1 H), 4.99−4.89

resulting mixture was stirred for 20 h. The reaction mixture was then

(

m, 2 H), 2.97−2.89 (m, 2 H), 2.30−2.22 (m, 1 H), 1.96−1.79 (m, 2

diluted with Et O (200 mL) followed by quenching with brine (100

2

13

H), 0.93 (d, J = 6.5 Hz, 3 H); C NMR (125 MHz, CDCl ) δ 144.6,

mL) and deionized H O (100 mL). The resulting mixture was

3

2

1

37.3, 128.9, 127.8, 126.9, 115.9, 86.3, 68.0, 38.3, 34.0, 17.1; HRMS

extracted with Et O (2 × 150 mL). The combined organic layers were

2

+

(

ES ) m/z (M + Na) : calcd for C H ONa, 365.1881; found,

washed with brine, dried with Na SO , and concentrated in vacuo.

25

26

2

4

365.1899.

Puriﬁcation by ﬂash chromatography on silica gel (10% Et O/

2

J

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Hexanes) aﬀorded the desired epoxide 28 as a pale yellow oil (5.71 g,

H), 0.89 (s, 9 H), 0.08 (s, 3 H), 0.00 (s, 3 H); ¹³C NMR (125 MHz,

7

3% over the 3 steps).

Procedures for Anion Relay Chemistry. Compound (+)-22. A

CDCl ) δ 138.5, 128.2, 128.1, 126.4, 109.08, 75.5, 69.1, 67.3, 43.9,

3

41.9, 37.2, 30.3, 30.0, 27.0, 26.2, 26.0, 25.7, 18.3, 17.9, −4.68, −4.87;

+

solution of n-BuLi (2.4 M, 672 μL, 1.613 mmol) in hexanes was added

to a stirred solution of 1,3-dithiane (193.9 mg, 1.613 mmol) in 4.5 mL

of THF and stirred for 5 min at room temperature. The solution was

then cooled to −20 °C, and a solution of epoxide 25 (300.0 mg, 1.512

mmol) in 1.5 mL of THF was added via cannula dropwise (followed

with a 1.5 mL rinse with THF). The resulting solution was slowly

warmed up to room temperature over 5 h. The solution was then

cannulated (followed by a 1.5 mL rinse with THF) into another ﬂask

containing CuI (384 mg, 2.016 mmol) that was stirred in 12.0 mL of

THF/HMPA mixture (1:1 in volume) at −20 °C for 20 min. The

resulting suspension was stirred at room temperature for 30 min to

obtain a homogeneous solution, which was then cannulated (followed

with a 1.5 mL rinse with THF) into another ﬂask containing a mixture

HRMS (ES ) m/z (M + Na) : calcd for C H O NaS Si, 481.2242;

23 42 3 2

found, 481.2245.

Compound (+)-50. A solution of n-BuLi (2.5 M, 4.53 mL, 11.33

mmol) in hexanes was added to a solution of 1,3-dithiane (1.36 g,

11.33 mmol) in 15 mL of THF at −20 °C and stirred for 2 h at this

temperature. A solution of epoxide 47 (1.66 g, 10.62 mmol) in 13.5

mL of THF (dried over anhydrous Na SO and degassed via freeze−

2

4

pump−thaw) was added via syringe dropwise (followed with a 6 mL

rinse with THF). The solution was stirred at −20 °C for 3 h and then

cooled to −78 °C, and HMPA (1.85 mL, 10.62 mmol) was added

dropwise. The resulting mixture was placed in a −40 °C cold bath and

stirred at this temperature for 1 h. The solution was then cooled to

−78 °C, and solid CuCN (476 mg, 5.31 mmol) was quickly added.

The resulting bright yellow suspension was stirred at −78 °C for 45

min, and then vinyl iodide 36 (1.9 g, 7.08 mmol) in 9 mL of THF

(dried over anhydrous Na SO ) was added via syringe dropwise

of vinyl iodide 26 (270.2 mg, 1.008 mmol), Pd(OAc) (22.6 mg, 0.101

2

mmol), and dppf (111.8 mg, 0.202 mmol) that has been stirred in 3.0

mL of THF at room temperature for 15 min. The resulting solution

was then stirred at room temperature for 17 h. The solution was then

quenched with saturated aqueous NH Cl (10 mL) and deionized H O

2

4

(followed with a 6 mL rinse with THF). The resulting yellow

suspension was placed in a +10 °C cold bath and stirred at this

temperature for 20 h to give a dark, clear solution, which was slowly

warmed to room temperature over 15 h. The solution was then added

to a solution of TBAF (1.0 M in THF, 42.5 mL, 42.5 mmol) and

stirred at room temperature for 2 h, followed by addition of saturated

aqueous NH Cl (50 mL) and deionized H O (50 mL). The resulting

4

2

(

10 mL). The resulting mixture was extracted with Et O (3 × 100

2

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

MgSO , and concentrated in vacuo. The crude product was puriﬁed by

ﬂash chromatography on silica gel (5% Et O/Hexanes) to aﬀord the

4

2

desired three-component adduct 22 as a pale yellow oil (375 mg, 0.817

4

2

mmol, 81%): [α]²⁰+21.41 (c 1.45, CH Cl ); IR (ﬁlm, cm ) 2935,

−1

mixture was extracted with Et O (3 × 150 mL). The combined organic

D

2

1

2

891, 2861, 1599, 1463, 1373, 1251, 1071, 934, 835, 775; H NMR

layers were washed with brine, dried with MgSO , and concentrated in

4

(

500 MHz, CDCl ) δ 6.40 (t, J = 11.4 Hz, 1 H), 6.05 (d, J = 11.7 Hz, 1

vacuo. The crude product was puriﬁed by ﬂash chromatography on

3

H), 5.41−5.33 (m, 1 H), 4.98 (dd, J = 8.6, 4.7 Hz, 1 H), 4.19−4.11

silica gel (30% Et O/Hexanes) to aﬀord the desired three-component

2

0

(

m, 1 H), 4.05−3.94 (m, 2 H), 3.60−3.53 (m, 1 H), 2.88−2.74 (m, 4

adduct 50 as a pale yellow oil (2.17 g, 6.30 mmol, 89%): [α] +4.61

(c 0.64, CH Cl ); IR (ﬁlm, cm ) 3448, 2984, 2930, 1423, 1369, 1214,

2 2

1155, 1060, 974, 909, 848; H NMR (500 MHz, CDCl ) δ 5.58−5.44

D

−1

H), 2.58−2.50 (m, 1 H), 2.46−2.37 (m, 1 H), 2.14−1.99 (m, 2 H),

1

.95−1.84 (m, 1 H), 1.80−1.70 (m, 1 H), 1.76 (s, 3 H), 1.43 (s, 3 H),

3

13

1

.35 (s, 3 H), 0.88 (s, 9 H), 0.08 (s, 3 H), −0.01 (s, 3 H); C NMR

(m, 2 H), 5.12 (s, 1 H), 4.90 (s, 1 H), 4.43−4.37 (m, 1 H), 4.23−4.18

(m, 1 H), 4.17−4.11 (m, 1 H), 4.03 (dd, J = 8.0, 6.0 Hz, 1 H), 3.61−

3.55 (m, 1 H), 2.95−2.80 (m, 5 H), 2.77−2.70 (m, 1 H), 2.42−2.35

(m, 1 H), 2.30−2.23 (m, 1 H), 2.16−2.09 (m, 1 H), 2.00−1.85 (m, 4

(

125 MHz, CDCl ) δ 140.9, 125.7, 125.1, 121.2, 109.1, 75.6, 69.1,

3

6

−

7.0, 43.9, 41.9, 31.7, 30.4, 29.9, 27.1, 26.2, 26.0, 25.8, 18.4, 18.3, −4.7,

+

4.9; HRMS (ES ) m/z (M + H) : calcd for C H O S Si, 459.2423;

23 43 3 2

found, 459.2422.

H), 1.42 (s, 3 H), 1.35 (s, 3 H); ¹³C NMR (125 MHz, CDCl ) δ

3

Compound (−)-37. A solution of n-BuLi (2.4 M, 381 μL, 0.914

mmol) in hexanes was added to a stirred solution of 1,3-dithiane

149.9, 130.8, 127.6, 111.5, 109.1, 75.6, 71.5, 69.0, 44.1, 41.3, 37.0, 35.6,

30.4, 30.1, 27.0, 26.1, 25.8; HRMS (ES ) m/z (M + Na) : calcd for

+

(

109.9 mg, 0.914 mmol) in 2.5 mL of THF and stirred for 5 min at

C H O NaS , 367.1378; found, 367.1390.

17

28

3

2

room temperature. The solution was then cooled to −20 °C, and a

solution of epoxide 25 (170 mg, 0.857 mmol) in 1 mL of THF was

added via cannula dropwise (followed with a 0.7 mL rinse with THF).

The resulting solution was slowly warmed up to room temperature

over 5 h. The solution was then cannulated (followed with a 0.5 mL

rinse with THF) into another ﬂask containing CuI (217.5 mg, 1.142

mmol) that has been stirred in 6.8 mL of a THF/HMPA mixture (1:1

in volume) at −20 °C for 20 min. The resulting suspension was stirred

at room temperature for 30 min to obtain a homogeneous solution,

which was then cannulated (followed with a 1.0 mL rinse with THF)

into another ﬂask containing a mixture of vinyl iodide 36 (153 mg,

Compound (−)-23. A solution of TBS-dithiane 27a (406 mg, 1.73

mmol) in 5.4 mL of THF was treated with a solution of n-BuLi (2.3 M,

0.826 mL, 1.9 mmol) in hexanes at room temperature and stirred for 5

min. The reaction mixture was then cooled to −40 °C, and a solution

of epoxide 28 (414 mg, 1.15 mmol) in 15 mL of Et O was added via

2

syringe dropwise. The mixture was stirred at −40 °C and monitored

by TLC (30% Et O/Hexanes). After 30 min, TLC analysis showed

2

complete consumption of dithiane. The reaction was then cooled to

−78 °C, and a solution of (S)-epichlorohydrin (266 mg, 2.87 mmol)

in 5 mL of Et O (dried over anhydrous Na SO ) was added dropwise

2

4

via syringe, followed by HMPA (0.327 mL, 1.72 mmol). The reaction

mixture was stirred at −78 °C for 5 min and then allowed to warm to 0

°C using an ice/water bath over 1 h. The cold bath was then removed,

and the reaction mixture was allowed to warm to room temperature

for about 1 h. Freshly prepared vinylmagnesium bromide (1.0 M, 3.5

mL, 3.5 mmol) in THF was added to a suspension of CuI (110 mg,

0

.571 mmol), Pd(OAc) (12.8 mg, 0.0571 mmol), and dppf (63.3 mg,

2

0

.114 mmol) that has been stirred in 1.5 mL of THF at rt for 15 min.

The resulting solution was then stirred at room temperature for 19 h.

The solution was then quenched with saturated aqueous NH Cl (5

mL) and deionized H O (5 mL). The resulting mixture was extracted

4

2

with Et O (3 × 50 mL). The combined organic layers were washed

0.58 mmol) in 11 mL of Et O at −78 °C via syringe. The reaction

2

with brine, dried with MgSO , and concentrated in vacuo. The crude

mixture containing the ARC product was then added via syringe over 5

min. The resulting mixture was stirred at −78 °C for 30 min, and the

reaction ﬂask was then placed in an ice/water bath at 0 °C and allowed

to warm to room temperature for over 1.5 h. An aqueous solution of

Rochelle’s salt (15% w/v) was ﬁnally added, and the resulting biphasic

mixture was stirred at room temperature for 20 min and then extracted

with EtOAc twice. The combined organic extracts were washed with

water and brine, dried over anhydrous Na SO , and concentrated in

4

product was puriﬁed by ﬂash chromatography on silica gel (5% Et O/

2

Hexanes) to aﬀord the desired three-component adduct 37 as a pale

2

0

yellow oil (212.2 mg, 0.463 mmol, 81%): [α]

−2.99 (c 0.82,

D

−1

CH Cl ); IR (ﬁlm, cm ) 2979, 2929, 2893, 2856, 1472, 1369, 1252,

210, 1155, 1069, 1004, 965, 935, 837, 777, 668; H NMR (500 MHz,

2

1

CDCl ) δ 6.43 (dd, J = 14.9, 11.3 Hz, 1 H), 5.8 (d, J = 11.1 Hz, 1 H),

3

5

4

3

2

.55 (dt, J = 14.9, 7.2 Hz, 1 H), 4.95 (dd, J = 8.0, 5.1 Hz, 1 H), 4.18−

.11 (m, 1 H), 4.05−4.00 (m, 1 H), 3.97 (dd, J = 8.6, 5.8 Hz, 1 H),

.60−3.54 (m, 1H), 2.88−2.77 (m, 4 H), 2.50−2.43 (m, 1H), 2.36−

.28 (m, 1 H), 2.15−2.07 (m, 1 H), 2.06−2.00 (m, 1 H), 1.94−1.84

2

4

vacuo. The crude material obtained was puriﬁed by silica gel column

chromatography (5−30% Et O/Hexanes) to aﬀord 23 as a colorless

2

20

oil (676 mg, 1.00 mmol, 87%): [α]

(ﬁlm, cm ) 3434, 3058, 2927, 2856, 1596, 1490, 1472, 1448, 1255,

−13.7 (c 0.65, CH Cl ); IR

D

2

−1

(

m, 1 H), 1.81−1.74 (m, 1 H), 1.71 (s, 3 H), 1.42 (s, 3 H), 1.35 (s, 3

K

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1

069, 909, 836, 808, 774, 745, 707, 633; H NMR (500 MHz, CDCl )

Hz, 1 H), 4.93 (dd, J = 9.0, 4.3 Hz, 1 H), 4.16−4.09 (m, 1 H), 4.00

(dd, J = 7.9, 5.9 Hz, 1 H), 3.85−3.75 (m, 2 H), 3.58−3.53 (m, 1 H),

2.57−2.38 (m, 2 H), 2.35−2.27 (m, 1 H), 1.99−1.91 (m, 1 H), 1.78

3

δ 7.44 (d, J = 7.7 Hz, 6 H), 7.32−7.19 (m, 9 H), 5.89−5.77 (m, 1 H),

5

3

(

.11−5.04 (m, 2 H), 4.16−4.08 (m, 1 H), 4.04−3.98 (m, 1 H), 3.93−

.89 (m, 1 H), 3.02−2.96 (m, 1 H), 2.89−2.69 (m, 4 H), 2.64−2.55

1

3

(s, 3 H), 1.66−1.59 (m, 1 H), 1.40 (s, 3 H), 1.34 (s, 3 H); C NMR

m, 1 H), 2.30−2.03 (m, 6 H), 2.00−1.85 (m, 3 H), 1.66−1.59 (m, 1

(125 MHz, CDCl ) δ 138.3, 128.6, 127.9, 126.9, 109.2, 75.6, 69.9,

3

+

H), 1.47−1.39 (m, 1 H), 1.05 (d, J = 6.5 Hz, 3 H), 0.88 (s, 9 H), 0.12

69.0, 61.4, 37.2, 36.9, 27.0, 25.8, 18.2; HRMS (ES ) m/z (M + Na) :

(

s, 3 H), 0.04 (s, 3 H); ¹³C NMR (125 MHz, CDCl ) δ 144.5, 135.1,

calcd for C H O Na, 279.1572; found, 279.1561.

3

14 24

4

1

28.9, 127.8, 126.9, 117.5, 86.4, 69.0, 68.6, 67.6, 51.5, 45.4, 45.3, 44.0,

Compound (+)-51. To a solution of alcohol 50 (1.56 g, 4.53 mmol)

+

4

3.0, 31.2, 26.5, 26.4, 26.3, 25.1, 18.7, 18.2, −3.0, −4.0; HRMS (ES )

in MeCN (150 mL) and deionized H O (15 mL) were added MeI

2

+

m/z (M + Na) : calcd for C H O NaSiS , 699.3338; found,

(4.2 mL, 67.92 mmol) and CaCO (6.8 g, 67.92 mmol). After stirring

40

56

3

2

3

6

99.3328.

at 60 °C for 5 h, the solution was then cooled to room temperature

and ﬁltered through a short pad of Celite. The resulting mixture was

extracted with EtOAc (2 × 200 mL). The combined organic layers

Synthesis of Mandelalide A Northern Hemisphere. Com-

pound (+)-34. A solution of TBAF (1.0 M, 0.305 mL, 0.305 mmol) in

THF was added to a stirred solution of compound 22 (55.9 mg, 0.122

mmol) in 2 mL of THF at room temperature. After stirring at room

were washed with brine, dried with MgSO , and concentrated in vacuo.

4

The crude was then taken up in 70 mL of MeOH, and NaBH (0.86 g,

4

temperature for 7 h, the solution was quenched with deionized H O

22.64 mmol) was added at 0 °C. After stirring for 30 min at room

2

(

10 mL). The resulting mixture was extracted with Et O (2 × 30 mL).

temperature, the solution was quenched with deionized H O (50 mL).

2

The combined organic layers were washed with brine, dried with

The resulting mixture was extracted with EtOAc (2 × 200 mL). The

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

and concentrated in vacuo. The crude product was puriﬁed by ﬂash

MgSO , and concentrated in vacuo. The crude product was puriﬁed by

ﬂash chromatography on silica gel (30% EtOAc/Hexanes) to aﬀord

the desired alcohol 34 as a pale yellow oil (39.9 mg, 0.116 mmol,

4

chromatography on silica gel (50−100% EtOAc/Hexanes) to aﬀord

5%): [α]²⁰+27.07(c 1.04, CH Cl ); IR (ﬁlm, cm ) 3452, 3033,

−1

20

9

2

1

4

diol 51 as a colorless oil (1.06 g, 4.14 mmol, 91%): [α] +22.35 (c

D

2

D

−

1

983, 2935, 2898, 1423, 1371, 1317, 1275, 1244, 1214, 1155, 1063,

002, 909, 849, 790, 755; H NMR (500 MHz, CDCl ) δ 6.37 (t, J =

0.25, CH Cl ); IR (ﬁlm, cm ) 3399, 2984, 2927, 2872, 1370, 1214,

2 2

1

3

1154, 1061, 973, 902; H NMR (500 MHz, CDCl ) δ 5.59−5.44 (m, 2

3

1.4 Hz, 1 H), 6.09 (d, J = 11.7 Hz, 1 H), 5.41−5.33 (m, 1 H), 5.06−

.98 (m, 1 H), 4.15−4.04 (m, 2 H), 4.03−3.95 (m, 1 H), 3.56−3.49

H), 5.12 (s, 1 H), 4.90 (s, 1 H), 4.34 (dd, J = 7.6, 3.9 Hz, 1 H), 4.17−

4.11 (m, 1 H), 4.02 (dd, J = 7.9, 6.1 Hz, 1 H), 3.88−3.78 (m, 2 H),

3.61−3.55 (m, 1 H), 2.86−2.78 (m, 1 H), 2.76−2.69 (m, 1 H), 2.53−

(

m, 1 H), 2.89−2.76 (m, 4 H), 2.55−2.46 (m, 1 H), 2.44−2.34 (m, 1

H), 2.15−2.02 (m, 3 H), 1.93−1.69 (m, 2 H), 1.79 (s, 3 H), 1.40 (s, 3

2.32 (m, 3 H), 2.31−2.24 (m, 1 H), 1.88−1.75 (m, 2 H), 1.41 (s, 3 H),

H), 1.32 (s, 3 H); ¹C NMR (125 MHz, CDCl ) δ 139.7, 125.7, 125.4,

3

13

3

1.35 (s, 3 H); C NMR (125 MHz, CDCl ) δ 150.4, 130.9, 127.5,

3

1

2

3

22.1, 109.1, 75.5, 69.0, 66.5, 43.9, 40.7, 31.7, 30.1, 30.0, 27.0, 26.0,

5.7, 18.3; HRMS (ES ) m/z (M + Na) : calcd for C H O S Na,

67.1378; found, 367.1371.

110.9, 109.1, 75.6, 74.8, 68.9, 61.6, 37.0, 36.9, 35.8, 27.0, 25.7; HRMS

+

1

7

28

3

2

(ES ) m/z (M + Na) : calcd for C H O Na, 279.1572; found,

14 24 4

279.1568.

Compound (−)-37a. A solution of TBAF (1.0 M, 1.23 mL, 1.23

Compound (−)-52. To a solution of diol 51 (800 mg, 3.12 mmol)

in 66 mL of MeCN were added 46 mL of pH 6.5 phosphate buﬀer,

which was stirred vigorously. To the mixture was added sequentially

pyridine-N-oxide (593 mg in 8 mL of MeCN, 6.24 mmol), citric acid

monohydrate (492 mg in 8 mL of pH 6.5 phosphate buﬀer, 2.34

mmol) in THF was added to a stirred solution of compound 37 (187.8

mg, 0.409 mmol) in 6 mL of THF at room temperature. After stirring

at room temperature for 3 h, the solution was quenched with

deionized H O (15 mL). The resulting mixture was extracted with

2

Et O (2 × 50 mL). The combined organic layers were washed with

mmol), Cu(OTf) (1.13 g in 8 mL of MeCN, 3.12 mmol) and solid

2

brine, dried with MgSO , and concentrated in vacuo. The crude

K OsO .2H O (230 mg, 0.624 mmol). The resulting mixture was

4

2

4

2

product was puriﬁed by ﬂash chromatography on silica gel (30%

stirred vigorously at room temperature for approximately 2 weeks, at

which time 600 mL of EtOAc was added and the organic layer was

separated. The aqueous layer was extracted with EtOAc (2 × 300 mL).

The combined organic layers were washed with brine, dried with

Na SO , and concentrated in vacuo. The crude product was quickly

EtOAc/Hexanes) to aﬀord the desired alcohol 37a as a pale yellow oil

2

0

(

9

136.7 mg, 0.397 mmol, 97%): [α] −12.86 (c 0.34, CH Cl ); IR

D

2

−1

ﬁlm, cm ) 3745, 2979, 2934, 2901, 1424, 1370, 1214, 1155, 1059,

61, 841, 668; H NMR (500 MHz, CDCl ) δ 6.43 (dd, J = 14.9, 11.3

1

3

2

4

Hz, 1 H), 5.87 (d, J = 11.1 Hz, 1 H), 5.58 (dt, J = 14.7, 7.2 Hz, 1 H),

puriﬁed by ﬂash chromatography on neutral alumina (1% H O/

2

5

3

2

1

2

.03 (bs, 1 H), 4.17−4.10 (m, 2 H), 4.02 (dd, J = 7.9, 5.9 Hz, 1 H),

.59−3.54 (m, 1 H), 2.93−2.81 (m, 4 H), 2.49−2.41 (m, 1 H), 2.36−

.28 (m, 1 H), 2.17−2.07 (m, 2 H), 1.95−1.80 (m, 2 H), 1.77 (s, 3 H),

EtOAc) to recover starting material 51 (88 mg, 0.34 mmol) and obtain

desired product 52 as a colorless oil (663 mg, 2.43 mmol, 78%, 88%

b.r.s.m.): [α]²⁰−68.87 (c 0.33, CH Cl ); IR (ﬁlm, cm ) 3421, 2985,

−1

D

2

.41 (s, 3 H), 1.35 (s, 3 H); ¹³C NMR (125 MHz, CDCl ) δ 137.3,

1

3

2935, 2871, 1666, 1371, 1219, 1158, 1058, 881; H NMR (500 MHz,

29.0, 127.8, 127.6, 109.1, 75.5, 69.1, 67.1, 44.1, 40.8, 37.2, 30.2, 30.1,

C D ) δ 4.77 (s, 1 H), 4.60 (s, 1 H), 4.37−4.28 (m, 2 H), 3.96−3.91

6

+

7.1, 26.1, 25.8, 17.9; HRMS (ES ) m/z (M + Na) : calcd for

(m, 1 H), 3.69−3.42 (m, 5 H), 2.81 (bs, 1 H), 2.34−2.26 (m, 1 H),

2.23−2.06 (m, 2 H), 1.76−1.68 (m, 1 H), 1.62−1.50 (m, 3 H), 1.43

(s, 3 H), 1.36 (s, 3 H); ¹³C NMR (125 MHz, C D ) δ 151.4, 108.7,

C H O S Na, 367.1378; found, 367.1387.

17

28

3 2

Compound (+)-38. To a solution of alcohol 37a (39.7 mg, 0.115

6

mmol) in MeCN (4 mL) and deionized H O (0.4 mL) were added

104.8, 82.1, 80.5, 74.0, 70.5, 70.2, 60.2, 38.5, 37.8, 35.1, 27.4, 26.0;

2

+

MeI (108 μL, 1.73 mmol) and CaCO (173.2 mg, 1.73 mmol). After

HRMS (ES ) m/z (M + Na) : calcd for C H O Na, 295.1521;

3

14 24 5

stirring at 65 °C for 6 h, the solution was then cooled to room

found, 295.1520.

temperature and ﬁltered through a short pad of Celite. The resulting

Compound (−)-52a. To a solution of diol 52 (400 mg, 1.47 mmol)

mixture was extracted with Et O (2 × 50 mL). The combined organic

in 24 mL of CH Cl at −78 °C were added sequentially 2,6-lutidine

2

layers were washed with brine, dried with MgSO , and concentrated in

(1.7 mL, 14.69 mmol) and TBSOTf (2.0 mL, 8.81 mmol) via syringe

dropwise. The resulting mixture was warmed to 0 °C and stirred at this

temperature for 4 h. The solution was quenched with saturated

4

vacuo. The crude was then taken up in 2 mL of MeOH, and NaBH₄

(

21.8 mg, 0.576 mmol) was added at 0 °C. After stirring for 1 h at

room temperature, the solution was quenched with deionized H O (2

aqueous NaHCO (20 mL). The resulting mixture was extracted with

2

3

mL). The resulting mixture was extracted with Et O (2 × 5 mL). The

EtOAc (2 × 100 mL). The combined organic layers were washed with

2

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

and concentrated in vacuo. The crude product was puriﬁed by ﬂash

chromatography on silica gel (50% EtOAc/Hexanes) to aﬀord diol 38

brine, dried with Na SO , and concentrated in vacuo. The crude

2

4

product was puriﬁed by ﬂash chromatography on silica gel (2−4%

EtOAc/Hexanes) to aﬀord the desired product 52a as a colorless oil

20

D

20

as a colorless oil (23.0 mg, 0.0897 mmol, 78%): [α] +36.47 (c 1.37,

(721 mg, 1.44 mmol, 98%): [α] −63.04 (c 0.38, CH Cl ); IR (ﬁlm,

D

2

−

1

−1

1

CH Cl ); IR (ﬁlm, cm ) 3855, 2985, 2937, 2881, 1438, 1372, 1215,

cm ) 2982, 2956, 2929, 2857, 1472, 1369, 1252, 1101, 836, 777; H

2

1

155, 1059, 966, 848, 790; H NMR (500 MHz, CDCl ) δ 6.41 (dd, J

NMR (500 MHz, C D ) δ 4.81 (bs, 1 H), 4.75 (bs, 1 H), 4.43−4.33

3

6

=

14.9, 11.3 Hz, 1 H), 5.85 (d, J = 11.1 Hz, 1 H), 5.56 (dt, J = 14.8, 7.4

(m, 2 H), 4.10−4.04 (m, 1 H), 3.92−3.83 (m, 3 H), 3.71 (dt, J = 9.90,

L

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

6

.30 Hz, 1 H), 3.41−3.35 (m, 1 H), 2.23−2.10 (m, 2 H), 2.04−1.95

the above aldehyde in 5 mL of THF was added via cannula dropwise,

(

m, 1 H), 1.86−1.77 (m, 1 H), 1.58−1.50 (m, 1 H), 1.44 (s, 3 H),

and the resulting mixture was stirred at −78 °C for 2.5 h. The solution

1

6

1

2

.40−1.33 (m, 1 H), 1.38 (s, 3 H), 1.06 (s, 9 H), 1.01 (s, 9 H), 0.25 (s,

was then quenched with saturated aqueous NH Cl (20 mL) and

4

H), 0.13 (s, 3 H), 0.12 (s, 3 H); ¹³C NMR (125 MHz, C D ) δ

allowed to warm to room temperature over 45 min. The resulting

mixture was extracted with EtOAc (3 × 100 mL). The combined

organic layers were washed with brine, dried with Na SO , and

6

51.9, 109.0, 104.3, 82.1, 78.2, 72.6, 72.3, 70.1, 60.5, 39.1, 37.6, 35.4,

7.5, 26.4, 26.2, 26.1, 18.60, 18.55, −3.8, −4.4, −5.05, −5.10; HRMS

2

4

+

(

5

ES ) m/z (M + Na) : calcd for C H O NaSi , 523.3251; found,

23.3263.

concentrated in vacuo. The crude product was puriﬁed by ﬂash

chromatography on silica gel (3% EtOAc/Hexanes) to aﬀord the

desired product 54 as a yellow oil (340.5 mg, 0.667 mmol, 77% over 2

steps): [α]²⁰−40.89 (c 0.29, CH Cl ); IR (ﬁlm, cm ) 2953, 2928,

26

52

5

2

Compound (−)-53. To a 150 mL ﬂask was added Wilkinson’s

−1

catalyst (76 mg, 0.082 mmol) under N . A solution of alkene 52a (822

mg, 1.64 mmol) in toluene (70 mL, degassed by freeze−pump−thaw)

was added via cannula, and the ﬂask was purged with 10 cycles of H₂

gas/vacuum. A H balloon was attached, and the resulting solution was

stirred vigorously for 21 h at room temperature. The solution was then

concentrated to obtain the crude as a mixture of diastereomers (d.r. =

2

D

2

1

2855, 1462, 1369, 1252, 1092, 1065, 837, 777; H NMR (500 MHz,

CDCl ) δ 6.35−6.29 (m, 1 H), 6.28−6.24 (m, 1 H), 4.29−4.23 (m, 1

3

H), 4.04 (dd, J = 7.7, 5.9 Hz, 1 H), 3.96−3.86 (m, 2 H), 3.72 (dt, J =

9.3, 6.4 Hz, 1 H), 3.53−3.47 (m, 1 H), 2.39−2.30 (m, 1 H), 2.27−2.20

(m, 2 H), 1.98 (dt, J = 12.5, 7.0 Hz, 1 H), 1.71−1.65 (m, 1 H), 1.55−

1.49 (m, 1 H), 1.40 (s, 3 H), 1.33−1.24 (m, 1 H), 1.34 (s, 3 H), 0.98

(d, J = 7.1 Hz, 3 H), 0.88 (s, 9 H), 0.09 (bs, 6 H); ¹C NMR (125

2

6

:1 by H NMR). Puriﬁcation by ﬂash chromatography on silica gel

3

(

2−3% EtOAc/Hexanes) aﬀorded the desired product 53 as a

20

colorless oil (685 mg, 1.36 mmol, 83%): [α]

−50.48 (c 0.27,

MHz, CDCl ) δ 139.1, 108.8, 83.5, 82.1, 80.1, 72.7, 71.8, 70.2, 37.2,

D

3

−

1

+

CH Cl ); IR (ﬁlm, cm ) 2953, 2928, 2856, 1461, 1379, 1252, 1095,

8

37.1, 35.8, 35.4, 27.3, 26.2, 26.0, 18.4, 15.5, −3.8, −4.6; HRMS (ES )

m/z (M + Na) : calcd for C H O NaSiI, 533.1560; found, 533.1570.

2

1

+

36, 776; H NMR (500 MHz, CDCl ) δ 4.29−4.21 (m, 1 H), 4.04

3

21 39

4

(

3

(

dd, J = 7.7, 5.9 Hz, 1 H), 3.91−3.82 (m, 2 H), 3.81−3.75 (m, 1 H),

.72−3.62 (m, 2 H), 3.51−3.44 (m, 1 H), 2.32−2.20 (m, 1 H), 1.97

dt, J = 12.4, 7.3 Hz, 1 H), 1.71−1.56 (m, 3 H), 1.54−1.47 (m, 1 H),

.39 (s, 3 H), 1.34 (s, 3 H), 1.24−1.18 (m, 1 H), 0.91 (d, J = 6.9 Hz, 3

Compound (−)-19a. To a solution of acetonide 54 (119.6 mg,

0.234 mmol) in a mixture of THF (2.6 mL) and MeCN (10.3 mL)

were added solid CeCl ·7H O (261.9 mg, 0.703 mmol) and a solution

3

2

1

of oxalic acid dihydrate (1 mg/mL in MeCN, 1.48 mL, 0.0117 mmol).

The suspension was stirred vigorously at room temperature for 30

13

H), 0.89 (s, 9 H), 0.88 (s, 9 H), 0.09 (s, 6 H), 0.05 (s, 6 H); C NMR

(

125 MHz, CDCl ) δ 108.7, 81.8, 78.4, 72.8, 72.0, 70.2, 61.4, 37.2,

min, then quenched with saturated aqueous NaHCO (10 mL), and

3

−

5

5.7, 35.5, 34.5, 27.3, 26.18, 26.15, 26.0, 18.5, 18.4, 15.8, −3.8, −4.6,

stirred for another 30 min. The resulting mixture was extracted with

+

5.1, −5.2; HRMS (ES ) m/z (M + Na) : calcd for C H O NaSi ,

EtOAc (2 × 50 mL). The combined organic layers were washed with

26

54

5

2

25.3408; found, 525.3417.

brine, dried with Na SO , and concentrated in vacuo. The crude

2 4

Compound (−)-53a. To a polyethylene bottle containing a solution

product was puriﬁed by ﬂash chromatography on silica gel (20%

of compound 53 (557 mg, 1.109 mmol) in 56 mL of THF at 0 °C was

added HF·pyridine (70%, 2.72 mL) via Eppendorf pipet. After stirring

for 4 h at 0 °C, the solution was quenched slowly with 130 mL of

EtOAc/Hexanes) to aﬀord diol 19a as a white solid (101 mg, 0.215

mmol, 92%): [α]²⁰

−29.09 (c 0.20, CH

Cl

2

); IR (ﬁlm, cm ) 3398,

−1

D

2

1

2959, 2926, 2854, 1461, 1254, 1090, 837, 777; H NMR (500 MHz,

saturated aqueous NaHCO . The resulting mixture was then diluted

CDCl

3

) δ 6.35−6.24 (m, 2 H), 4.01−3.87 (m, 4 H), 3.64−3.57 (m, 2

3

with 50 mL of EtOAc and stirred vigorously at room temperature for

5 min. The organic layer was separated, and the aqueous layer was

H), 3.48−3.40 (m, 1 H), 2.42−2.33 (m, 1 H), 2.27−2.22 (m, 2 H),

2.08−2.00 (m, 2 H), 1.81−1.72 (m, 1 H), 1.56−1.48 (m, 1 H), 1.29−

1.23 (m, 1 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.90 (s, 9 H), 0.11 (s, 6 H);

1

extracted with EtOAc (2 × 200 mL). The combined organic layers

13

were washed with saturated aqueous CuSO and brine, dried with

C NMR (125 MHz, CDCl ) δ 138.9, 83.8, 81.3, 80.2, 73.9, 69.3,

4

3

+

Na SO , and concentrated in vacuo. The crude product was puriﬁed by

67.4, 37.2, 36.3, 36.1, 35.8, 26.1, 18.3, 15.5, −4.1, −4.7; HRMS (ES )

m/z (M + H) : calcd for C H O SiI, 471.1428; found, 471.1434.

2

4

+

ﬂash chromatography on silica gel (20% EtOAc/Hexanes) to aﬀord

the desired product 53a as a colorless oil (414 mg, 1.065 mmol, 96%):

18

36

4

Compound (−)-19. To a solution of diol 19a (104.4 mg, 0.222

2

0

−1

[

2

α] −46.72 (c 0.52, CH Cl ); IR (ﬁlm, cm ) 3434, 2960, 2929,

mmol) in 16 mL of CH Cl at 0 °C were added sequentially a solution

D

2

1

851, 1462, 1378, 1251, 1062, 837, 777; H NMR (500 MHz, CDCl )

of imidazole (48 mg/mL in CH Cl , 1.63 mL, 1.15 mmol) and a

3

2 2

δ 4.26−4.19 (m, 1 H), 4.04 (dd, J = 7.6, 6.0 Hz, 1 H), 3.98 (ddd, J =

solution of TBSCl (80 mg/mL in CH Cl , 1.63 mL, 0.865 mmol) via

2 2

syringe dropwise. The resulting mixture was stirred at room

temperature for 4.5 h. The solution was quenched with saturated

1

3

1

0.5, 7.4, 2.6 Hz, 1 H), 3.95−3.90 (m, 1 H), 3.82−3.74 (m, 3 H),

.51−3.46 (m, 1 H), 2.53 (bs, 1 H), 2.33 (dt, J = 14.5, 7.2 Hz, 1 H),

.99−1.91 (m, 1 H), 1.75−1.63 (m, 2 H), 1.60−1.52 (m, 2 H), 1.39

aqueous NH Cl (25 mL). The resulting mixture was extracted with

4

(

0

s, 3 H), 1.36−1.28 (m, 1 H), 1.33 (s, 3 H), 0.94 (d, J = 7.1 Hz, 3 H),

EtOAc (2 × 50 mL). The combined organic layers were washed with

.89 (s, 9 H), 0.10 (s, 3 H), 0.09 (s, 3 H); ¹³C NMR (125 MHz,

CDCl ) δ 108.8, 82.2, 81.4, 72.7, 70.9, 70.1, 62.1, 37.4, 35.9, 35.1, 33.2,

brine, dried with Na SO , and concentrated in vacuo. The crude

2

4

3

product was puriﬁed by ﬂash chromatography on silica gel (3%

EtOAc/Hexanes) to aﬀord the northern hemisphere 19 as a colorless

+

2

7.2, 26.1, 25.9, 18.3, 15.5, −4.0, −4.5; HRMS (ES ) m/z (M + H) :

2

0

calcd for C H O Si, 389.2723; found, 389.2739.

oil (125 mg, 0.213 mmol, 96%): [α] −23.14 (c 0.58, CHCl ); IR

20

41

5

D

3

−

1

Compound (−)-54. To a solution of alcohol 53a (336.7 mg, 0.866

mmol) in 30 mL of CH Cl at 0 °C were added NaHCO (291.1 mg,

(ﬁlm, cm ) 3456, 2955, 2925, 2850, 1731, 1257, 1117, 837, 777, 668;

H NMR (500 MHz, CDCl ) δ 6.35−6.30 (m, 1 H), 6.28−6.23 (m, 1

1

2

3

.466 mmol) and Dess-Martin periodinane (735 mg, 1.733 mmol).

H), 3.96−3.89 (m, 2 H), 3.88−3.77 (m, 2 H), 3.55−3.44 (m, 2 H),

2.96 (d, J = 2.8 Hz, 1 H), 2.39−2.30 (m, 1 H), 2.27−2.20 (m, 2 H),

2.05−1.97 (m, 1 H), 1.60−1.50 (m, 2 H), 1.31−1.22 (m, 1 H), 0.98

(d, J = 6.9 Hz, 3 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.11 (s, 3 H), 0.10 (s,

The resulting mixture was stirred at 0 °C for 5 min. The cold bath was

then removed, and the solution was stirred at room temperature for

another 2 h. The solution was quenched with saturated aqueous

NaHCO (30 mL) and saturated aqueous Na S O (30 mL). The

3 H), 0.06 (bs, 6 H); ¹³C NMR (125 MHz, CDCl ) δ 139.1, 83.5,

3

2

3

resulting mixture was extracted with EtOAc (2 × 100 mL). The

81.9, 80.2, 73.0, 68.8, 67.8, 37.2, 36.7, 35.9, 35.8, 26.2, 26.1, 18.44,

+

combined organic layers were washed with brine, dried with Na SO ,

18.41, 15.5, −4.0, −4.7, −5.2; HRMS (ES ) m/z (M + H) : calcd for

2

4

and concentrated. The obtained crude was passed through a short pad

of silica gel (wash with EtOAc) and concentrated in vacuo to aﬀord the

desired aldehyde, which was used directly in the next step.

C H O Si I, 585.2292; found, 585.2287.

24

50

4

2

Synthesis of Mandelalide A Southern Hemisphere. Com-

pound (−)-60. To a solution containing alcohol 23 (1.617 g, 2.39

A solution of NaHMDS (1.0 M, 4.07 mL, 4.07 mmol) in THF was

added dropwise to a solution of Ph PCH I (2.30 g, 4.33 mmol) in 10

mmol) and Et N (1.032 mL, 7.41 mmol) in 12.5 mL of Et O was

3

2

added MsCl (0.555 mL, 7.17 mmol) at 0 °C. The resulting mixture

was stirred at room temperature for 16 h and monitored by TLC for

complete consumption of 23. To the reaction mixture was added

TBAF (1.0 M in THF, 12.0 mL, 12.0 mmol), and the mixture was

placed under reﬂux at 60 °C for 48 h. The reaction mixture was then

3

2 2

mL of THF at 0 °C, and the resulting solution was stirred at this

temperature for another 15 min. The solution was then cooled to −78

°

C, and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU,

0.87 mL, 7.19 mmol) was added via syringe dropwise. A solution of

M

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

cooled to room temperature and diluted with EtOAc and water. The

organic layer was separated, washed with saturated aqueous NaHCO₃,

water, and brine, dried over anhydrous Na SO , and ﬁltered. The

organic solvents were removed under reduced pressure to give crude

material, which was puriﬁed by silica gel column chromatography

and ﬁltered. The ﬁltrate was concentrated under reduced pressure.

The residue was ﬁltered through a pad of silica gel (20% Et O/

2

Hexanes) and concentrated in vacuo to aﬀord crude product, which

was directly used in the next step without further puriﬁcation.

To a mixture of the above crude in 14 mL of methanol was added

pyridinium p-toluenesulfonate (1.3 g, 5.2 mmol) at room temperature.

The resulting mixture was stirred at room temperature overnight. The

2

4

(

10−20% Et O/Hexanes) to aﬀord 60 as a colorless foam (0.812 g,

2

20

−1

1

3

1

.49 mmol, 62%): [α]

−8.67 (c 1.05, CH Cl ); IR (ﬁlm, cm )

D

2

057, 2916, 1684, 1653, 1636, 1557, 1490, 1448, 1424, 1374, 1339,

reaction was quenched with saturated aqueous NaHCO and diluted

3

1

266, 1220, 1152, 1070, 1002, 910, 742, 706; H NMR (500 MHz,

with water. The aqueous layer was extracted with EtOAc twice. The

combined organic extracts were washed with saturated aqueous

NaHCO and brine, dried over anhydrous Na SO , and ﬁltered. The

CDCl ) δ 7.44 (d, J = 7.5 Hz, 6 H), 7.32−7.19 (m, 9 H), 5.85−5.74

3

(

m, 1 H), 5.10−5.00 (m, 2 H), 3.80−3.66 (m, 2 H), 3.02 (dd, J = 8.5,

3

2

4

5

4

1

4

.4 Hz, 1 H), 2.90−2.82 (m, 3 H), 2.74−2.68 (m, 1 H), 2.30−2.08 (m,

ﬁltrate was concentrated under reduced pressure to give the crude

material, which was puriﬁed by silica gel chromatography (25−30%

EtOAc/Hexanes) to aﬀord primary alcohol 62a as a colorless oil (0.38

g, 1.14 mmol, 83%): [α]²⁰+9.11 (c 0.51, CH Cl ); IR (ﬁlm, cm )

H), 2.07−1.97 (m, 3 H), 1.62−1.49 (m, 4 H), 1.27−1.19 (m, 1 H),

.01 (d, J = 6.5 Hz, 3 H); ¹³C NMR (125 MHz, CDCl ) δ 144.6,

3

−1

34.7, 128.9, 127.8, 126.9, 117.0, 86.2, 72.3, 70.6, 68.7, 48.3, 43.9, 42.9,

D

2

+

1

0.2, 39.9, 30.5, 26.1, 26.0, 17.5; HRMS (ES ) m/z (M + Na) : calcd

3415, 2919, 2850, 1613, 1513, 1248, 1173, 1073, 1037, 916, 822; H

for C H O NaS , 567.2367; found, 567.2372.

NMR (500 MHz, CDCl ) δ 7.25 (d, J = 8.5 Hz, 2 H), 6.89 (d, J = 8.5

34

40

2

3

Compound (−)-61a. To a solution of 60 (0.45 g, 0.826 mmol) in

Hz, 2 H), 5.84−5.76 (m, 1 H), 5.11−5.06 (m, 2 H), 4.49 (s, 2 H), 3.82

(s, 3 H), 3.58−3.52 (m, 2 H), 3.41−3.35 (m, 3 H), 2.39−2.34 (m, 1

H), 2.28−2.22 (m, 1 H), 2.07−2.04 (m, 1 H), 2.00−1.97 (m, 1 H),

1.86−1.80 (m, 1 H), 1.63−1.57 (m, 1 H), 1.43−1.38 (m, 1 H), 1.30−

1.18 (m, 2 H), 0.91 (d, J = 7.0 Hz, 3 H); ¹³C NMR (125 MHz,

MeCN (10 mL) and water (3.4 mL) were added CaCO (372 mg,

3

.71 mmol) and MeI (3.0 mL, 49 mmol), followed by stirring at room

temperature over 2 days for complete consumption of 60 by TLC. The

suspension was then diluted with Et O and water. The aqueous layer

2

was extracted with Et O twice, and the combined organic extracts were

CDCl ) δ 159.3, 134.3, 130.7, 129.3, 117.7, 114.0, 75.6, 75.5, 74.3,

2

3

+

dried over anhydrous Na SO₄and ﬁltered. The ﬁltrate was

69.4, 68.5, 55.4, 41.7, 40.6, 39.1, 37.5, 34.9, 18.4; HRMS (ES ) m/z

2

+

concentrated under reduced pressure to give material, which was

(M + H) : calcd for C H O , 335.2222; found, 335.2221.

20

31

4

puriﬁed by silica gel column chromatography (10−20% Et O/

Compound (+)-62. Hoveyda−Grubbs’ second generation catalyst

(40 mg, 0.064 mmol) was added to a solution of 62a (0.268 g, 0.801

mmol) and methyl acrylate (0.433 mL, 4.8 mmol) in 12 mL of

CH Cl . The mixture was stirred for 18 h at room temperature. The

2

Hexanes) to aﬀord ketone 61a (0.364 g, 0.80 mmol, 97%) as a

colorless oil: [α]²⁰−13.8 (c 1.0, CH Cl ); IR (ﬁlm, cm ) 3057,

−1

D

2

9

7

2

1

916, 1719, 1642, 1596, 1491, 1449, 1359, 1329, 1221, 1154, 1067,

20, 764, 746, 707, 632; H NMR (500 MHz, CDCl ) δ 7.44 (d, J =

2

1

resulting mixture was then concentrated to obtain the crude (E/Z >

3

1

.5 Hz, 6 H), 7.32−7.20 (m, 9 H), 5.85−5.75 (m, 1 H), 5.12−5.06 (m,

H), 3.61−3.51 (m, 2 H), 3.03−3.00 (m, 1 H), 2.96−2.93 (m, 1 H),

.41−2.16 (m, 6 H), 2.10−2.02 (m, 1 H), 1.79−1.70 (m, 1 H), 1.34−

20:1 based on H NMR integration), which was puriﬁed by silica gel

chromatography (20−50% EtOAc/Hexanes) to aﬀord the desired

2

0

single isomer 62 as a colorless oil (0.284 g, 0.727 mmol, 91%): [α]

D

13

−1

.21 (m, 1 H), 0.99 (d, J = 6.5 Hz, 3 H); C NMR (125 MHz,

+5.96 (c 0.65, CH Cl ); IR (ﬁlm, cm ) 3448, 2918, 1719, 1658, 1613,

1586, 1614, 1438, 1247, 1071, 823; H NMR (500 MHz, CDCl ) δ

2 2

1

CDCl ) δ 207.6, 144.5, 133.7, 128.9, 127.8, 127.0, 117.8, 86.3, 76.5,

3

+

7

5.0, 68.5, 48.5, 47.4, 40.6, 30.6, 17.4; HRMS (ES ) m/z (M + Na) :

7.25 (d, J = 9.0 Hz, 2 H), 6.98−6.91 (m, J = 1 H), 6.89 (d, J = 9.0 Hz,

2 H), 5.90 (d, J = 15.5 Hz, 1 H), 4.49 (s, 2 H), 3.82 (s, 3 H), 3.75 (s, 3

H), 3.57−3.37 (m, 5 H), 2.51−2.46 (m, 1 H), 2.42−2.36 (m, 1 H),

2.05−1.97 (m, 2 H), 1.86−1.80 (m, 1 H), 1.64−1.58 (m, 1 H), 1.38−

calcd for C H O Na, 477.2406; found, 477.2391.

31

34

3

Compound (+)-61. A solution of 61a (0.325 g, 0.715 mmol) in 9

mL of MeOH was cooled to −5 °C with an ice/brine bath. Solid

1

3

NaBH (0.135 g, 3.57 mmol) was added, and the reaction mixture was

1.35 (m, 1 H), 1.30−1.21 (m, 2 H), 0.92 (d, J = 7.0 Hz, 3 H); C

4

stirred at −5 °C for 40 min for complete consumption of 61a by TLC.

The reaction was then quenched with 1.0 M aqueous HCl and diluted

NMR (125 MHz, CDCl ) δ 166.9, 159.3, 144.7, 130.6, 129.3, 123.5,

3

114.0, 75.2, 74.5, 74.1, 69.5, 68.4, 55.4, 51.6, 41.0, 38.9, 38.7, 37.5,

+

with saturated aqueous NH Cl. The aqueous layer was extracted with

34.2, 18.0; HRMS (ES ) m/z (M + Na) : calcd for C H O Na,

4

22 32 6

ethyl acetate twice, and the combined organic extracts were dried over

415.2097; found, 415.2097.

anhydrous Na SO and ﬁltered. The ﬁltrate was concentrated under

Compound (−)-65. To a solution of alcohol 62 (276 mg, 0.703

2

4

reduced pressure to give the crude material, which was puriﬁed by

silica gel chromatography (10−25% EtOAc/Hexanes) to aﬀord the

desired product 61 as a colorless oil (0.278 g, 0.609 mmol, 85%). The

mmol) in 13 mL of CH Cl at 0 °C were added NaHCO (354.5 mg,

2

3

4.22 mmol) and Dess-Martin periodinane (894.8 mg, 2.11 mmol).

The resulting mixture was stirred at 0 °C for 5 min. The cold bath was

then removed, and the solution was stirred at room temperature for

another 3 h. The solution was quenched with saturated aqueous

NaHCO (15 mL) and saturated aqueous Na S O (25 mL). The

minor diastereomer was also obtained as a colorless oil (0.026 g,

−1

0

3

.0766 mmol, 8%): [α]²⁰+6.02 (c 0.51, CH Cl ); IR (ﬁlm, cm )

D

2

1

376, 2923, 2850, 1636, 1448, 1375, 1323, 1071, 706; H NMR (500

3

2

3

MHz, CDCl ) δ 7.44 (d, J = 7.5 Hz, 6 H), 7.30−7.21 (m, 9 H), 5.82−

resulting mixture was extracted with EtOAc (2 × 100 mL). The

3

5

.77 (m, 1 H), 5.07−5.01 (m, 2 H), 3.74−3.71 (m, 1 H), 3.30−3.22

m, 2 H), 3.03−3.00 (m, 1 H), 2.88 (dd, J = 8.5, 2.0 Hz, 1 H), 2.32−

.28 (m, 1 H), 2.18−2.14 (m, 1 H), 2.03−1.99 (m, 1 H), 1.95−1.92

combined organic layers were washed with brine, dried with Na SO ,

2

4

(

2

and concentrated. The obtained crude was passed through a short pad

of silica gel (wash with EtOAc) and concentrated in vacuo to aﬀord the

desired aldehyde, which was used directly in the next step.

A solution of NaHMDS (1.0 M, 0.914 mL, 0.914 mmol) in THF

was added dropwise to a solution of sulfone 64 (236.4 mg, 1.055

mmol) in 6.5 mL of THF at −78 °C, and the resulting solution was

stirred at this temperature for another 30 min. A solution of the above

aldehyde in 12 mL of THF was added via cannula dropwise, and the

resulting mixture was slowly warmed up to room temperature over 20

(

m, 1 H), 1.88−1.84 (m, 1 H), 1.65−1.59 (m, 1 H), 1.39 (d, J = 8.5, 5

Hz, 1 H), 1.27−1.22 (m, 1 H), 1.14−1.07 (m, 2 H), 0.99 (d, J = 7.0

Hz, 3 H); ¹³C NMR (125 MHz, CDCl ) δ 144.6, 134.9, 128.9, 127.8,

3

1

26.9, 116.8, 86.3, 75.2, 73.4, 68.7, 68.5, 41.9, 40.9, 40.6, 40.3, 30.6,

+

17.6; HRMS (ES ) m/z (M + Na) : calcd for C H O Na, 479.2562;

31 36 3

found, 479.2561.

Compound (+)-62a. To a solution of alcohol 61 (0.63 g, 1.38

mmol) in 6.5 mL of DMF was added tert-BuOK (0.744 g, 6.9 mmol)

at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, followed

by addition of p-methoxybenzyl bromide (0.82 mL, 5.52 mmol). The

obtained mixture was then allowed to warm to room temperature and

stirred overnight at which point TLC analysis showed complete

consumption of 61. The reaction was quenched with water. The

aqueous layer was extracted with EtOAc. The organic extract was

washed with water (twice) and brine, dried over anhydrous Na SO ,

h. The solution was then quenched with deionized H O (20 mL), and

2

the resulting mixture was extracted with EtOAc (3 × 50 mL). The

combined organic layers were washed with brine, dried with Na SO ,

2

4

and concentrated in vacuo. The crude product was puriﬁed by ﬂash

chromatography on silica gel (5% EtOAc/Hexanes) to aﬀord the

desired product 65 as a colorless oil (245.9 mg, 0.633 mmol, 90% over

2 steps): [α]²⁰−7.86 (c 0.73, CH Cl ); IR (ﬁlm, cm ) 3073, 2999,

−1

D

2

2919, 2851, 1722, 1658, 1612, 1586, 1513, 1437, 1355, 1248, 1173,

2

4

N

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1

8

=

074, 1037, 912, 822, 762; H NMR (500 MHz, CDCl ) δ 7.25 (d, J =

was added a solution of DDQ (recrystallized over CHCl , 19.8 mg,

3

.3 Hz, 2 H), 7.01−6.93 (m, 1 H), 6.88 (d, J = 8.3 Hz, 2 H), 5.87 (d, J

0.0873 mmol) in 1.5 mL of CH Cl dropwise at 0 °C. After stirring at

2

15.7 Hz, 1 H), 5.73 (ddd, J = 17.3, 10, 7.5 Hz, 1 H), 4.99−4.87 (m, 2

0 °C for 2.5 h, the mixture was then quenched with pH 7 phosphate

buﬀer (5 mL), and the resulting mixture was extracted with CH Cl (3

H), 4.48 (s, 2 H), 3.80 (s, 3 H), 3.73 (s, 3 H), 3.56−3.47 (m, 1 H),

2

3

1

.40−3.26 (m, 2 H), 2.50−2.62 (m, 1 H), 2.38−2.29 (m, 2 H), 2.06−

× 30 mL). The combined organic layers were washed with brine, dried

.97 (m, 2 H), 1.66 (dt, J = 14.0, 7.3 Hz, 1 H), 1.37−1.29 (m, 1 H),

with Na SO , and concentrated in vacuo. The crude product was

2

4

13

.28−1.13 (m, 2 H), 0.99 (d, J = 6.5 Hz, 3 H); C NMR (125 MHz,

puriﬁed by ﬂash chromatography on silica gel (10% EtOAc/Hexanes)

to aﬀord the desired product 70 as a colorless oil (22.7 mg, 0.0276

mmol, 95%): [α]²⁰−30.53 (c 0.40, CH Cl ); IR (ﬁlm, cm ) 3424,

CDCl ) δ 167.0, 159.3, 145.6, 144.6, 130.7, 129.3, 123.0, 114.0, 112.5,

3

−1

7

4.4, 74.3, 73.8, 69.4, 55.4, 51.6, 42.7, 39.0, 38.1, 38.0, 34.2, 20.0;

HRMS (ES ) m/z (M + Na) : calcd for C H O Na, 411.2147;

D

2

+

3075, 2951, 2928, 2856, 1719, 1655, 1462, 1362, 1255, 1177, 1102,

23

32

5

1

found, 411.2150.

1006, 911, 837, 777, 668; H NMR (500 MHz, CDCl ) δ 6.99−6.91

3

Compound (−)-20. To a solution of methyl ester 65 (208 mg,

.535 mmol) in 16.1 mL of THF was added aqueous LiOH solution

1.0 M, 5.35 mL) dropwise, and the resulting mixture was stirred at

room temperature for 34 h. The reaction mixture was then diluted

(m, 1 H), 6.36−6.30 (m, 1 H), 6.29−6.24 (m, 1 H), 5.88 (d, J = 15.7

Hz, 1 H), 5.71 (ddd, J = 17.3, 10.0, 7.5 Hz, 1 H), 5.05−4.98 (m, 1 H),

4.98−4.90 (m, 2 H), 3.95−3.89 (m, 1 H), 3.82−3.74 (m, 3 H), 3.71−

3.66 (m, 2 H), 3.43−3.29 (m, 2 H), 2.50−2.43 (m, 1 H), 2.38−2.29

(m, 3 H), 2.27−2.21 (m, 1 H), 2.04−1.90 (m, 3 H), 1.88−1.80 (m, 1

H), 1.70−1.63 (m, 2 H), 1.46 (bs, 1 H), 1.38−1.26 (m, 2 H), 1.21−

1.07 (m, 2 H), 1.02−0.96 (m, 6 H), 0.94−0.85 (m, 1 H), 0.87 (s, 9 H),

0

(

with deionized H O (50 mL) and EtOAc (50 mL) and cooled to 0 °C,

2

followed by dropwise addition of aqueous HCl solution (1.0 M, 5.35

mL) to give an acidic solution (pH ≈ 2 with pH paper). The resulting

mixture was extracted with EtOAc (3 × 100 mL). The combined

organic layers were washed with brine, dried with Na SO , and

1

3

0.86 (s, 9 H), 0.06−0.00 (m, 12 H); C NMR (125 MHz, CDCl ) δ

3

166.1, 145.2, 144.5, 139.1, 123.7, 112.7, 83.6, 81.8, 80.1, 74.2, 73.7,

72.0, 71.2, 68.3, 64.6, 42.6, 41.1, 41.0, 38.8, 37.1, 35.7, 35.3, 34.4, 34.1,

2

4

concentrated in vacuo. The crude product was puriﬁed by ﬂash

chromatography on silica gel (20% EtOAc/Hexanes) to aﬀord the

desired product 20 as a colorless oil (186.5 mg, 0.498 mmol, 93%):

+

26.2, 26.0, 20.1, 18.39. 18.35, 15.5, −3.8, −4.7, −5.2; HRMS (ES ) m/

+

z (M + H) : calcd for C38

H

O

7

Si

2

I, 821.3705; found, 821.3697.

70

20

−1

[α]

−6.36 (c 0.27, CH Cl ); IR (ﬁlm, cm ) 3069, 2920, 2853,

Compound (−)-71. To a ﬂask containing activated 4A MS powder

(380 mg) were added sugar donor 21 (90.1 mg, 0.175 mmol) in 1.2

D

2

1

696, 1654, 1612, 1513, 1420, 1357, 1248, 1173, 1073, 913, 821; H

NMR (500 MHz, CDCl ) δ 11.50−10.50 (bs, 1 H), 7.25 (d, J = 8.5

mL of Et

mmol) in 0.56 mL of Et

room temperature for 1 h. The ﬂask was the cooled to −78 °C, and a

solution of Tf O (25.2 μL, 0.15 mmol) in 0.3 mL of Et O was added

dropwise followed by stirring at −78 °C for 20 min. A solution of

alcohol 70 (20.4 mg, 0.0248 mmol) in 2.4 mL of Et O was added via

2

O and 2,6-di-tert-butyl-4-methylpyridine (77.0 mg, 0.375

3

Hz, 2 H), 7.13−7.03 (m, 1 H), 6.88 (d, J = 8.5 Hz, 2 H), 5.88 (d, J =

2

O, and the resulting mixture was stirred at

1

5.7 Hz, 1 H), 5.73 (ddd, J = 17.3, 10.1, 7.5 Hz, 1 H), 4.99−4.88 (m, 2

H), 4.49 (s, 2 H), 3.8 (s, 3 H), 3.57−3.49 (m, 1 H), 3.42−3.34 (m, 1

2

H), 3.34−3.27 (m, 1 H), 2.53−2.45 (m, 1 H), 2.41−2.29 (m, 2 H),

2

1

.06−1.98 (m, 2 H), 1.70−1.63 (m, 1 H), 1.37−1.29 (m, 1 H), 1.28−

.12 (m, 2 H), 0.99 (d, J = 6.7 Hz, 3 H); C NMR (125 MHz,

2

13

cannula dropwise. The resulting mixture was stirred at −78 °C for 1 h,

CDCl ) δ 170.8, 159.3, 148.3, 144.6, 130.7, 129.3, 122.5, 114.0, 112.6,

then at −40 °C for 2 h, and at −35 °C for 1 h. The ﬂask was then

3

7

4.3, 74.1, 73.8, 69.5, 55.5, 42.7, 39.0, 38.12, 38.09, 34.2, 20.0; HRMS

cooled to −78 °C, and the reaction was quenched with deionized H O

2

+

(

ES ) m/z (M + Na) : calcd for C H O Na, 397.1991; found,

(7 mL), diluted with EtOAc (10 mL), and allowed to warm to room

temperature. The reaction mixture was ﬁltered and extracted with

EtOAc (3 × 20 mL). The combined organic layers were washed with

brine, dried with Na SO , and concentrated in vacuo. The crude

22

30

5

3

97.1993.

Fragment Union and Completion of Mandelalide A Total

Synthesis. (−)-Compound 67. To a solution of carboxylic acid 20

31.0 mg, 0.0827 mmol) in 0.56 mL of toluene were added a solution

of Et N (13%v/v in toluene, 0.8 mL, 0.744 mmol) and a solution of

2

4

(

product was puriﬁed by ﬂash chromatography on silica gel (3−5%

3

EtOAc/Hexanes) to aﬀord the desired product 71 as a colorless oil

2

0

2

,4,6-trichlorobenzoyl chloride (4.6%v/v in toluene, 0.56 mL, 0.165

(26.1 mg, 0.0216 mmol, 87%): [α] −46.92 (c 0.40, CH Cl ); IR

D

2

−1

mmol) via syringe dropwise. The solution was stirred at room

(ﬁlm, cm ) 2954, 2928, 2856, 1720, 1656, 1471, 1362, 1255, 1097,

1049, 1005, 837, 776, 668; H NMR (500 MHz, CDCl ) δ 7.00−6.91

1

temperature for 5 h, at which time a solution of alcohol 19 (32.2 mg,

3

0.0551 mmol) in 2 mL of toluene was added via cannula. A solution of

(m, 1 H), 6.35−6.30 (m, 1 H), 6.29−6.23 (m, 1 H), 5.88 (d, J = 15.7

Hz, 1 H), 5.76−5.67 (m, 1 H), 5.05−4.98 (m, 1 H), 4.99−4.89 (m, 2

H), 4.88 (d, J = 2.2 Hz, 1 H), 3.95−3.90 (m, 1 H), 3.87−3.84 (m, 1

H), 3.80−3.66 (m 5 H), 3.60−3.52 (m, 2 H), 3.45 (s, 3 H), 3.42−3.30

(m, 3 H), 2.50−2.42 (m, 1 H), 2.38−2.31 (m, 3 H), 2.26−2.22 (m, 1

H), 2.05−1.91 (m, 3 H), 1.88−1.81 (m, 1 H), 1.71−1.61 (m, 2 H),

1.36−1.11 (m, 8 H), 1.02−0.96 (m, 6 H), 0.92 (s, 9 H), 0.89 (s, 9 H),

DMAP (20.2 mg, 0.165 mmol) in 0.56 mL of toluene was added, and

the resulting mixture was stirred for 27 h at room temperature. The

solution was then quenched with saturated aqueous NH Cl (5 mL),

4

and the resulting mixture was extracted with EtOAc (3 × 20 mL). The

combined organic layers were washed with brine, dried with Na SO ,

2

4

and concentrated in vacuo. The crude product was puriﬁed by ﬂash

chromatography on silica gel (5% EtOAc/Hexanes) to aﬀord the

desired product 67 as a colorless oil (44.1 mg, 0.0468 mmol, 85%):

1

3

0.87 (s, 9 H), 0.86 (s, 9 H), 0.12−0.00 (m, 24 H); C NMR (125

MHz, CDCl ) δ 166.1, 145.2, 144.6, 139.1, 123.6, 112.6, 83.6, 81.8,

3

2

0

−1

[

α] −26.97 (c 0.35, CH Cl ); IR (ﬁlm, cm ) 2955, 2926, 2855,

80.1, 74.2, 73.7, 73.5, 73.4, 72.0, 71.2, 70.5, 64.6, 58.9, 42.7, 39.3, 39.0,

37.6, 37.1, 35.7, 35.3, 34.4, 34.0, 26.5, 26.3, 26.2, 26.0, 20.0, 18.8, 18.5,

18.4, 18.3, 18.2, 15.5, −3.6, −3.8, −3.99, −4.04, −4.8, −5.2; HRMS

D

2

1

8

6

1

4

3

2

717, 1655, 1614, 1559, 1539, 1511, 1459, 1363, 1250, 1173, 1090,

37, 776; H NMR (500 MHz, CDCl ) δ 7.25 (d, J = 8.5 Hz, 2 H),

1

3

+

.99−6.91 (m, 1 H), 6.88 (d, J = 8.5 Hz, 2 H), 6.35−6.29 (m, 1 H),

.27−6.23 (m, 1 H), 5.88 (d, J = 15.7 Hz, 1 H), 5.71 (ddd, J = 17.3,

0.1, 7.5 Hz, 1 H), 5.05−4.99 (m, 1 H), 4.98−4.89 (m, 2 H), 4.52−

.45 (m, 2 H), 3.95−3.89 (m, 1 H), 3.80 (s, 3 H), 3.79−3.74 (m, 2 H),

.71−3.66 (m, 2 H), 3.56−3.49 (m, 1 H), 3.41−3.27 (m, 2 H), 2.51−

.43 (m, 1 H), 2.38−2.29 (m, 3 H), 2.27−2.21 (m, 1 H), 2.06−1.97

(ES ) m/z (M + Na) : calcd for C H O NaSi I, 1231.5990; found,

57 109 11 4

1231.6014.

Compound (−)-71a. To a solution of compound 71 (25.0 mg,

0.0207 mmol) in 3 mL of anhydrous DMF (degassed via freeze−

pump−thaw) was added a solid mixture of Pd(OAc) (8.4 mg, 0.0373

2

mmol) and Cs CO (13.5 mg, 0.0414 mmol), followed by a solution

2

3

(

m, 3 H), 1.88−1.81 (m, 1 H), 1.71−1.62 (m, 2 H), 1.37−1.13 (m, 5

of Et N (4.3 μL, 0.031 mmol) in 0.43 mL of DMF. The resulting

3

13

H), 1.01−0.97 (m, 6 H), 0.87 (bs, 18 H), 0.05−0.01 (m, 12 H);

C

solution was stirred at room temperature for 2 days. The reaction was

NMR (125 MHz, CDCl ) δ 166.1, 159.3, 145.3, 144.6, 139.1, 130.8,

quenched with deionized H O (10 mL) and extracted with EtOAc (3

3

2

1

6

2

29.3, 123.6, 114.0, 112.6, 83.5, 81.8, 80.2, 74.4, 74.3, 73.8, 72.0, 71.2,

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

9.4, 64.7, 55.4, 42.7, 39.0, 38.1, 38.0, 37.1, 35.7, 35.3, 34.4, 34.1, 26.2,

with Na SO , and concentrated in vacuo. The crude product was

2

4

+

6.0, 20.0, 18.39, 18.35, 15.5, −3.8, −4.8, −5.2; HRMS (ES ) m/z (M

puriﬁed by ﬂash chromatography on silica gel (3−4% EtOAc/

Hexanes) to aﬀord the desired product 71a as a colorless oil (17.9 mg,

0.0165 mmol, 80%): [α]²⁰−13.44 (c 0.03, CH Cl ); IR (ﬁlm, cm )

+

H) : calcd for C H O Si I, 941.4280; found, 941.4301.

46

78

8

2

−1

Compound (−)-70. To a solution of 67 (27.4 mg, 0.0291 mmol) in

D

2

0.7 mL of CH Cl and 0.156 mL of pH 7 phosphate buﬀer (0.5 M)

2952, 2928, 2892, 2856, 1720, 1653, 1471, 1389, 1359, 1254, 1126,

2

O

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1

6

5

3

096, 1047, 863, 838, 777, 668; H NMR (500 MHz, CDCl ) δ 6.97−

Compound (−)-73b. To a solution of carboxylic acid 20 (39.0 mg,

3

.89 (m, 1 H), 6.28 (dd, J = 14.9, 11.1 Hz, 1 H), 6.05−5.94 (m, 2 H),

.46 (dd, J = 14.9, 8.9 Hz, 1 H), 5.28 (td, J = 10.7, 4.8 Hz, 1 H), 5.07−

.01 (m, 1 H), 4.89 (d, J = 2.4 Hz, 1 H), 4.02−3.96 (m, 1 H), 3.88−

.84 (m, 1 H), 3.83−3.72 (m, 2 H), 3.66−3.29 (m, 11 H), 2.50−2.30

0.104 mmol) in 0.70 mL of toluene were added a solution of Et N

3

(13%v/v in toluene, 1.00 mL, 0.937 mmol) and a solution of 2,4,6-

trichlorobenzoyl chloride (4.6%v/v in toluene, 0.700 mL, 0.208 mmol)

via syringe dropwise. The solution was stirred at room temperature for

5 h, at which time a solution of alcohol 72 (37.5 mg, 0.0694 mmol) in

2.5 mL of toluene was added via cannula. A solution of DMAP (25.4

mg, 0.208 mmol) in 0.700 mL of toluene was added, and the resulting

mixture was stirred for 24 h at room temperature. The solution was

(

m, 5 H), 2.05−1.98 (m, 1 H), 1.98−1.88 (m, 3 H), 1.73−1.56 (m, 3

H), 1.31−1.19 (m, 7 H), 1.02 (d, J = 6.7 Hz, 3 H), 0.94−0.91 (m, 12

H), 0.89 (s, 9 H), 0.87 (s, 9 H), 0.85 (s, 9 H), 0.10 (s, 9 H), 0.08 (s, 3

13

H), 0.01 (s, 3 H), 0.01 (s, 6 H), −0.05 (s, 3 H); C NMR (125 MHz,

CDCl ) δ 166.1, 145.8, 140.5, 130.2, 128.1, 125.1, 123.7, 83.3, 81.3,

then quenched with saturated aqueous NH

resulting mixture was extracted with EtOAc (3 × 20 mL). The

combined organic layers were washed with brine, dried with Na SO ,

Cl (5 mL), and the

3

4

7

3

1

(

1

3.9, 73.7, 73.34, 73.30, 72.8, 71.6, 70.6, 64.7, 58.9, 43.6, 39.7, 39.4,

8.1, 36.7, 36.5, 36.0, 33.5, 31.4, 29.9, 26.4, 26.2, 26.0, 18.9, 18.8, 18.5,

8.4, 18.3, 18.2, 14.7, −3.7, −4.0, −4.1, −5.0, −5.27, −5.32; HRMS

2

4

and concentrated in vacuo. The crude product was puriﬁed by ﬂash

chromatography on silica gel (10% EtOAc/hexanes) to aﬀord the

desired product 73b as a colorless oil (55.4 mg, 0.0618 mmol, 89%):

+

ES ) m/z (M + H) : calcd for C H O Si , 1081.7047; found,

57 109 11 4

081.7057.

−)-Mandelalide A (5). To a solution of 71a (7.0 mg, 0.0065

mmol) in 0.9 mL of THF in a polypropylene tube at 0 °C were added

.9 mL of pyridine and 0.9 mL of HF·Pyridine complex (70% HF)

dropwise via Eppendorf pipet. The resulting solution was stirred at 0

C for 5 min. The cold bath was then removed, and the resulting

solution was stirred at room temperature for another 29 h. The

reaction was then quenched with 20 mL of sat. aq. NaHCO solution

slowly and stirred at room temperature for 30 min. The organic phase

was extracted with CH Cl (3 × 30 mL). The combined organic layers

were dried with Na SO and concentrated in vacuo. The crude product

was puriﬁed by ﬂash chromatography on silica gel (4% MeOH/

CH Cl ) to aﬀord the product 5 as colorless amorphous solid (3.8 mg,

.00608 mmol, 94%) which displayed spectral properties identical in

all respects to those reported for the natural product: [α] −53.92 (c

.25, MeOH); IR (ﬁlm, cm ) 3433, 2961, 2920, 2852, 1717, 1656,

2

0

−1

[

1

α] −22.71 (c 0.48, CH Cl ); IR (ﬁlm, cm ) 2956, 2927, 2853,

(

D

2

1

744, 1722, 1654, 1613, 1513, 1463, 1355, 1249, 1172, 1088, 836; H

NMR (500 MHz, CDCl ) δ 7.25 (d, J = 8.5 Hz, 2 H), 7.01−6.93 (m, 1

0

3

H), 6.87 (d, J = 8.5 Hz, 2 H), 6.34−6.29 (m, 1 H), 6.28−6.24 (m, 1

H), 5.88 (d, J = 15.7 Hz, 1 H), 5.77−5.67 (m, 1 H), 5.26−5.19 (m, 1

H), 4.99−4.87 (m, 2 H), 4.49 (s, 2 H), 4.3 (dd, J = 11.8, 3.7 Hz, 1 H),

°

4

3

.12 (dd, J = 11.9, 5.4 Hz, 1 H), 3.96−3.90 (m, 1 H), 3.80 (s, 3 H),

.80−3.74 (m, 2 H), 3.57−3.49 (m, 1 H), 3.41−3.34 (m, 1 H), 3.34−

.27 (m, 1 H), 2.52−2.44 (m, 1 H), 2.38−2.20 (m, 7 H), 2.06−1.96

3

2

(

m, 3 H), 1.91−1.84 (m, 1 H), 1.69−1.55 (m, 4 H), 1.37−1.12 (m, 4

2

4

H), 1.01−0.96 (m, 6 H), 0.93 (t, J = 7.4 Hz, 3 H), 0.87 (s, 9 H), 0.04

(

1

s, 3 H), 0.02 (s, 3 H); ¹³C NMR (125 MHz, CDCl ) δ 173.4, 165.9,

3

2

59.3, 145.9, 144.6, 138.9, 130.7, 129.3, 123.1, 114.0, 112.6, 83.7, 81.6,

0

2

0

80.2, 74.4, 74.2, 73.7, 71.0, 69.4, 69.1, 65.5, 55.4, 42.7, 39.0, 38.11,

38.07, 37.1, 36.2, 35.7, 35.2, 34.5, 34.1, 26.1, 20.0, 18.5, 18.3, 15.5,

D

−1

0

1

+

1

13.8, −3.8, −4.8; HRMS (ES ) m/z (M + H) : calcd for C44

97.3834; found, 897.3843.

Compound (−)-73a. To a solution of 73b (46.0 mg, 0.0513 mmol)

in 1.3 mL of CH Cl and 0.275 mL of pH 7 phosphate buﬀer (0.5 M)

H O SiI,

70 9

461, 1374, 1315, 1222, 1180, 1105, 1043, 731, 604; H NMR (600

MHz, CDCl , residual solvent peak set at δ 7.24 ppm) δ 6.97 (ddd, J =

5.1, 10.4, 4.6 Hz, 1 H), 6.28 (dd, J = 14.3, 11.4 Hz, 1 H), 6.05 (t, J =

0.8 Hz, 1 H), 6.01 (d, J = 15.4 Hz, 1 H), 5.45 (dd, J = 14.7, 10.3 Hz, 1

H), 5.28 (td, J = 10.5, 5.7 Hz, 1 H), 5.25−5.20 (m, 1 H), 5.02 (s, 1 H),

8

3

1

2

was added a solution of DDQ (recrystallized over CHCl , 34.9 mg,

3

0

°

.154 mmol) in 2.6 mL of CH Cl dropwise at 0 °C. After stirring at 0

2 2

4

3

2

1

.0−3.95 (m, 1 H), 3.85−3.78 (m, 2 H), 3.71−3.65 (m, 1 H), 3.66−

.59 (m, 3 H), 3.46 (s, 3 H), 3.44−3.29 (m, 5 H), 2.63−2.57 (m, 1 H),

.57−2.49 (m, 1 H), 2.43−2.19 (m, 7 H), 2.05−1.99 (m, 2 H), 1.91−

.85 (m, 2 H), 1.76 (t, J = 12.7 Hz, 1 H), 1.63−1.43 (m, 2 H), 1.26 (d,

C for 2.5 h, the mixture was then quenched with pH 7 phosphate

buﬀer (10 mL), and the resulting mixture was extracted with CH Cl

2

(

3 × 30 mL). The combined organic layers were washed with brine,

dried with Na SO , and concentrated in vacuo. The crude product was

2

4

J = 6.2 Hz, 3 H), 1.25−1.15 (m, 4 H), 1.02 (d, J = 7.0 Hz, 3 H), 0.85

puriﬁed by ﬂash chromatography on silica gel (10−20% EtOAc/

hexanes) to aﬀord the desired product 73a as a colorless oil (38.7 mg,

(

d, J = 6.6 Hz, 3 H); ¹³C NMR (125 MHz, CDCl , residual solvent

3

peak set at δ 77.23 ppm) δ 167.4, 147.1, 141.5, 131.3, 126.9, 123.9,

23.1, 94.2, 83.2, 81.0, 80.8, 74.2, 73.9, 73.1, 73.0, 72.5, 72.3, 71.7,

8.2, 66.1, 59.1, 43.1, 39.7, 38.8, 37.6, 37.4, 36.8, 34.2, 34.1, 31.1, 18.3,

7.7, 14.5; HRMS (ES ) m/z (M + Na) : calcd for C H O Na,

47.3407; found, 647.3411.

Total Synthesis of Mandelalide L and Analogs. Compound

−)-72. To a solution of diol 19a (25.0 mg, 0.053 mmol) in 2 mL of

CH Cl at room temperature were added sequentially a solution of

,3,5-collidine (38.8 mg/mL in CH Cl , 1.05 mL, 0.333 mmol) and a

solution of butyryl chloride (22.8 mg/mL in CH Cl , 1.05 mL, 0.224

20

−1

0

3

1

.0498 mmol, 97%): [α] −29.36 (c 0.60, CH Cl ); IR (ﬁlm, cm )

D

2

1

6

1

6

449, 3069, 2962, 2929, 2854, 1723, 1656, 1467, 1364, 1310, 1256,

172, 1090, 1046, 987, 906, 837, 778; H NMR (500 MHz, CDCl ) δ

1

3

+

33

52 11

7.00−6.92 (m, 1 H), 6.34−6.24 (m, 2 H), 5.88 (d, J = 15.7 Hz, 1 H),

5

(

.76−5.65 (m, 1 H), 5.25−5.19 (m, 1 H), 4.98−4.88 (m, 2 H), 4.30

dd, J = 11.8, 3.7 Hz, 1 H), 4.11 (dd, J = 11.7, 5.4 Hz, 1 H), 3.97−3.90

(

m, 1 H), 3.85−3.72 (m, 3 H), 3.44−3.30 (m, 2 H), 2.50−2.43 (m, 1

2

H), 2.38−2.21 (m, 7 H), 2.03−1.83 (m, 4 H), 1.70−1.52 (m, 5 H),

1.38−1.23 (m, 2 H), 1.21−1.07 (m, 2 H), 1.01−0.96 (m, 6 H), 0.93 (t,

2

2 2

13

2

J = 7.4 Hz, 3 H), 0.86 (s, 9 H), 0.04 (s, 3 H), 0.01 (s, 3 H); C NMR

mmol) via syringe. The resulting mixture was stirred at room

temperature for 7 h. The solution was quenched with saturated

aqueous NH Cl. The resulting mixture was extracted with EtOAc. The

(

8

125 MHz, CDCl ) δ 173.4, 165.9, 145.8, 144.5, 138.9, 123.2, 112.7,

3

3.7, 81.6, 80.2, 74.1, 73.7, 70.9, 69.1, 68.2, 65.5, 42.6, 41.1, 41.0, 38.8,

4

37.1, 36.2, 35.6, 35.2, 34.5, 34.1, 26.1, 20.0, 18.5, 18.3, 15.4, 13.8, −3.8,

combined organic layers were washed with brine, dried with Na SO ,

+

2

4

−4.8; HRMS (ES ) m/z (M + H) : calcd for C H O SiI, 777.3259;

36

62

8

and concentrated in vacuo. The crude product was puriﬁed by ﬂash

chromatography on silica gel (10% EtOAc/hexanes) to aﬀord the

desired product 72 as a colorless oil (27.2 mg, 0.0504 mmol, 95%):

α] −25.46 (c 0.44, CH Cl ); IR (ﬁlm, cm ) 3466, 2957, 2932,

852, 1738, 1461, 1386, 1254, 1181, 1092, 999, 837, 778; H NMR

found, 777.3242.

Compound (−)-73. To a ﬂask containing activated 4A MS powder

700 mg) were added sugar donor 21 (165.8 mg, 0.322 mmol) in 2.2

(

20

−1

[

2

(

4

D

2

mL of Et O and 2,6-di-tert-butyl-4-methylpyridine (141.7 mg, 0.375

2

1

mmol) in 1.1 mL of Et O, and the resulting mixture was stirred at

2

500 MHz, CDCl ) δ 6.35−6.29 (m, 1 H), 6.29−6.25 (m, 1 H), 4.12−

room temperature for 1 h. The ﬂask was the cooled to −78 °C, and a

3

.04 (m, 2 H), 4.01−3.84 (m, 4 H), 3.33 (bs, 1 H), 2.41−2.34 (m, 1

solution of Tf O (46.4 μL, 0.276 mmol) in 0.56 mL of Et O was added

2

H), 2.33 (t, J = 7.4 Hz, 2 H), 2.27−2.22 (m, 2 H), 2.06−1.99 (m, 1

dropwise; the mixture was stirred at −78 °C for 20 min. A solution of

H), 1.74−1.62 (m, 3 H), 1.59−1.52 (m, 1 H), 1.30−1.22 (m, 1 H),

alcohol 73a (35.7 mg, 0.046 mmol) in 4.5 mL of Et O was added via

2

0

(

8

1

.98 (d, J = 6.9 Hz, 3 H), 0.95 (t, J = 7.4 Hz, 3 H), 0.89 (s, 9 H), 0.11

cannula dropwise. The resulting mixture was stirred at −78 °C for 1 h,

s, 6 H); ¹³C NMR (125 MHz, CDCl ) δ 173.9, 138.9, 83.7, 81.4,

3

then at −40 °C for 2 h, and at −35 °C for 1 h. The ﬂask was then

0.2, 73.3, 68.7, 67.0, 37.1, 36.6, 36.2, 35.9, 35.8, 26.1, 18.6, 18.3, 15.5,

3.8, −4.1, −4.7; HRMS (ES ) m/z (M + Na) : calcd for

C H O NaSiI, 563.1666; found, 563.1667.

cooled to −78 °C, and the reaction was quenched with deionized H O

2

+

(15 mL), diluted with EtOAc (20 mL), and allowed to warm to room

temperature. The reaction mixture was ﬁltered and extracted with

22

41

5

P

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

EtOAc (3 × 40 mL). The combined organic layers were washed with

brine, dried with Na SO , and concentrated in vacuo. The crude

product was puriﬁed by ﬂash chromatography on silica gel (5%

puriﬁed by ﬂash chromatography on silica gel (20−40% EtOAc/

hexanes) to aﬀord the desired product 76 as a colorless oil (7.9 mg,

2

4

20

0.0081 mmol, 65% over 2 steps): [α] −27.35 (c 0.20, CH Cl ); IR

D

2

−1

EtOAc/Hexanes) to aﬀord the desired product 73 as a colorless oil

(ﬁlm, cm ) 3449, 2961, 2927, 2856, 1720, 1657, 1462, 1362, 1254,

1095, 1046, 897, 837, 777, 668; H NMR (500 MHz, CDCl ) δ 7.02−

2

0

1

(

1

6

5

47.2 mg, 0.0405 mmol, 88%): [α] −41.94 (c 0.60, CH Cl ); IR

D

2

3

−1

ﬁlm, cm ) 2956, 2928, 2854, 1725, 1657, 1460, 1254, 1165, 1096,

6.94 (m, 1 H), 6.27 (dd, J = 14.9, 11.3 Hz, 1 H), 6.05−5.97 (m, 2 H),

5.48 (dd, J = 14.9, 8.7 Hz, 1 H), 5.29 (td, J = 10.5, 5.2 Hz, 1 H), 5.14−

5.08 (m, 1 H), 4.89 (d, J = 2.6 Hz, 1 H), 4.01−3.95 (m, 1 H), 3.88−

3.84 (m, 1 H), 3.82−3.73 (m, 3 H), 3.65−3.52 (m, 4 H), 3.45 (s, 3 H),

3.44−3.40 (m, 1 H), 3.37−3.30 (m, 2 H), 2.47−2.32 (m, 5 H), 2.07−

1.99 (m, 1 H), 1.98−1.88 (m, 3 H), 1.80−1.72 (m, 1 H), 1.64−1.49

(m, 2 H), 1.32−1.19 (8 H), 1.01 (d, J = 6.9 Hz, 3 H), 0.95−0.91 (m,

12 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.13−0.09 (m, 9 H), 0.08 (s, 3 H),

1

052, 837, 777; H NMR (500 MHz, CDCl ) δ 7.01−6.93 (m, 1 H),

3

.34−6.24 (m, 2 H), 5.88 (d, J = 15.7 Hz, 1 H), 5.77−5.68 (m, 1 H),

.25−5.19 (m, 1 H), 4.99−4.85 (m, 3 H), 4.30 (dd, J = 11.8, 3.5 Hz, 1

H), 4.12 (dd, J = 11.8, 5.3 Hz, 1 H), 3.96−3.90 (m, 1 H), 3.87−3.83

(

3

1

(

0

3

1

6

2

−

m, 1 H), 3.82−3.69 (m, 3 H), 3.60−3.52 (m, 2 H), 3.45 (s, 3 H),

.42−3.30 (m, 3 H), 2.49−2.41 (m, 1 H), 2.38−2.21 (m, 7 H), 2.04−

.92 (m, 3 H), 1.91−1.83 (m, 1 H), 1.68−1.53 (m, 4 H), 1.35−1.13

1

3

m, 7 H), 1.02−0.96 (m, 6 H), 0.95−0.90 (m, 12 H), 0.89 (s, 9 H),

0.04 (s, 3 H), −0.03 (s, 3 H); C NMR (125 MHz, CDCl ) δ 167.1,

3

.86 (s, 9 H), 0.11−0.09 (m, 9 H), 0.08 (s, 3 H), 0.04 (s, 3 H), 0.02 (s,

146.8, 140.6, 130.3, 128.0, 124.9, 123.3, 82.8, 81.8, 81.4, 73.8, 73.5,

73.3, 73.2, 73.0, 72.8, 70.6, 66.1, 58.9, 43.5, 39.7, 39.3, 38.0, 36.5, 36.3,

35.6, 33.5, 31.3, 29.9, 26.4, 26.22, 26.16, 18.9, 18.8, 18.5, 18.3, 18.2,

14.8, −2.8, −3.7, −4.0, −4.1, −5.0; HRMS (ES ) m/z (M + Na) :

calcd for C H O Si Na, 989.6002; found, 989.6014.

H); ¹³C NMR (125 MHz, CDCl ) δ 173.4, 165.9, 145.9, 144.5,

3

38.9, 123.1, 112.6, 83.7, 81.6, 80.2, 74.1, 73.7, 73.4, 73.3, 70.9, 70.5,

9.2, 65.5, 58.9, 42.7, 39.3, 39.0, 37.6, 37.1, 36.2, 35.7, 35.2, 34.5, 34.0,

6.4, 26.2, 26.1, 19.9, 18.8, 18.5, 18.3, 18.2, 15.5, 13.8, −2.7, −3.6,

+

51

94 11

3

+

3.8, −4.0, −4.1, −4.8; HRMS (ES ) m/z (M + H) : calcd for

The known compound 79 was obtained as a side product (in less

than 10% yield) during the conversion of 74 to 76 and was subjected

to global deprotection to yield seco-mandelalide A methyl ester

(−)-80: to a solution of 79 (10.0 mg, 0.010 mmol) in 0.8 mL of THF

in a polypropylene tube at 0 °C were added 0.8 mL of pyridine and 0.8

mL of HF·Pyridine complex (70% HF) dropwise via Eppendorf pipet.

The resulting solution was stirred at 0 °C for 5 min. The cold bath was

then removed, and the resulting solution was stirred at room

temperature for another 16 h. The reaction was then quenched with

20 mL of sat. aq. NaHCO₃solution slowly and stirred at room

temperature for 30 min. The organic phase was extracted with CH Cl

C H O Si I, 1165.5724; found, 1165.5740.

55

102 12

3

Compound 74. To a solution of 73 (45.0 mg, 0.0386 mmol) in 5

mL of anhydrous DMF (degassed via freeze−pump−thaw) was added

a solid mixture of Pd(OAc) (15.6 mg, 0.0695 mmol) and Cs CO

2

3

(

25.2 mg, 0.0772 mmol), followed by a solution of Et N (8.1 μL, 0.058

3

mmol) in 0.40 mL of DMF. The resulting solution was stirred at room

temperature for 2 days. The reaction was quenched with deionized

H O (20 mL) and extracted with EtOAc (3 × 40 mL). The combined

2

organic layers were washed with brine, dried with Na SO , and

2

4

concentrated in vacuo. The crude product was ﬁltered through a short

pad of silica gel and concentrated to obtain ca. 42.0 mg of crude 74,

which was used directly in the next step without further puriﬁcation.

Compound (−)-75. To a solution of ca. 8.5 mg of the crude

product mixture of 74 in 1.0 mL of THF in a polypropylene tube at 0

2

4

(3 × 30 mL). The combined organic layers were dried with Na SO

2

and concentrated in vacuo. The crude product was puriﬁed by ﬂash

chromatography on silica gel (8% MeOH/CH Cl ) to aﬀord the

2

desired product 80 as colorless waxy solid (4.0 mg, 0.0061 mmol,

61%): [α]²⁰−48.07 (c 0.33, MeOH); IR (ﬁlm, cm ) 3391, 2924,

−1

°

C were added 1.0 mL of pyridine and 1.0 mL of HF·Pyridine complex

D

1

(

70% HF) dropwise via Eppendorf pipet. The resulting solution was

2857, 1721, 1658, 1447, 1373, 1322, 1277, 1106, 1042, 992; H NMR

stirred at 0 °C for 5 min. The cold bath was then removed, and the

resulting solution was stirred at room temperature for another 28 h.

The reaction was then quenched with 20 mL of sat. aq. NaHCO₃

solution slowly and stirred at room temperature for 30 min. The

organic phase was extracted with CH Cl (3 × 30 mL). The combined

(500 MHz, CDCl ) δ 6.97 (m, 1 H), 6.26 (dd, J = 14.9, 11.1 Hz, 1 H),

3

6.04 (t, J = 11.1 Hz, 1 H), 5.89 (d, J = 15.7 Hz, 1 H), 5.59 (m, 1 H),

5.33 (m, 1 H), 5.02 (s, 1 H), 4.07−3.99 (m, 1 H), 3.98−3.91 (m, 1 H),

3.74 (s, 3 H), 3.69−3.60 (m, 4 H), 3.56−3.49 (m, 1 H), 3.48 (s, 1 H),

3.44−3.30 (m, 6 H), 2.51−2.31 (m, 7 H), 2.30−2.22 (m, 1 H), 2.11−

2.05 (m, 1 H), 2.00−1.89 (m, 3 H), 1.71−1.50 (m, 4 H), 1.43−1.33

(m, 3 H), 1.30 (d, J = 5.9 Hz, 3 H), 1.19−1.10 (m, 2 H), 1.02 (d, J =

6.3 Hz, 3 H), 0.99 (d, J = 6.9 Hz, 3 H); ¹³C NMR (125 MHz,

2

organic layers were dried with Na SO and concentrated in vacuo. The

2

4

crude product was puriﬁed by RP18 HPLC (10−90% MeCN-H O,

2

0

.05% formic acid) to aﬀord the product 75 as colorless amorphous

20

solid (4.2 mg, 0.0060 mmol, 77% over 2 steps): [α] −53.42 (c 0.13,

MeOH); IR (ﬁlm, cm ) 3424, 2963, 2920, 2882, 1724, 1658, 1459,

1

CD OD) δ 168.6, 147.4, 141.7, 131.0, 127.4, 125.1, 123.7, 96.6, 83.8,

D

3

−1

83.0, 82.6, 75.4, 74.9, 74.7, 74.3, 72.2, 71.9, 70.1, 69.9, 68.0, 59.3, 52.0,

44.1, 40.3, 39.6, 38.5, 38.2, 37.04, 36.99, 34.7, 30.6, 20.8, 18.1, 15.6;

1

365, 1317, 1261, 1218, 1175, 1106, 1044, 984, 814; H NMR (600

+

MHz, CDCl , residual solvent peak set at 7.24 ppm) δ 6.95 (ddd, J =

HRMS (ES ) m/z (M + Na) : calcd for C H O Na, 679.3669;

3

34 56 12

1

5.2, 9.9, 5.0 Hz, 1 H), 6.26 (dd, J = 14.9, 10.9 Hz, 1 H), 6.05 (t, J =

0.9 Hz, 1 H), 5.95 (d, J = 15.8 Hz, 1 H), 5.44 (dd, J = 14.8, 9.8 Hz, 1

found, 679.3696.

Compound (−)-77. To a solution of compound 76 (5.0 mg, 0.0052

mmol) in 1.5 mL of CH Cl at room temperature were added

H), 5.35 (d, J = 11.0 Hz, 1 H), 5.27 (td, J = 10.8, 5.4 Hz, 1 H), 5.02 (s,

2

1

3

H), 4.35 (dd, J = 11.9, 3.9 Hz, 1 H), 4.07 (dd, J = 11.9, 4.3 Hz, 1 H),

.98 (t, J = 9.9 Hz, 1 H), 3.86−3.79 (m, 1 H), 3.71−3.59 (m, 3 H),

.46 (s, 3 H), 3.43−3.28 (m, 5 H), 2.56−2.48 (m, 1 H), 2.43−2.23

sequentially a solution of 2,3,5-collidine (19.0 mg/mL in CH Cl , 0.30

2 2

mL, 0.047 mmol) and a solution of valeroyl chloride (12.0 mg/mL in

CH Cl , 0.30 mL, 0.030 mmol) via syringe. The resulting mixture was

2

(

m, 8 H), 2.06−1.97 (m, 2 H), 1.92−1.84 (m, 2 H), 1.74−1.67 (m, 1

stirred at room temperature for 3 h. The solution was quenched with

H), 1.66−1.41 (m, 5 H), 1.27 (d, J = 6.2 Hz, 3 H), 1.24−1.14 (m, 4

H), 1.03 (d, J = 6.6 Hz, 3 H), 0.92 (t, J = 7.4 Hz, 3 H), 0.85 (d, J = 6.5

saturated aqueous NH Cl. The resulting mixture was extracted with

4

EtOAc. The combined organic layers were washed with brine, dried

Hz, 3 H); ¹³C NMR (125 MHz, CDCl , residual solvent peak set at

with Na SO , and concentrated in vacuo. The crude product was

3

2

4

7

9

5

1

6

7.0 ppm) δ 173.3, 165.8, 146.6, 141.4, 131.0, 126.7, 123.6, 122.7,

3.9, 82.9, 80.8, 80.5, 74.0, 73.7, 72.8, 72.6, 72.3, 71.4, 67.9, 67.7, 65.1,

8.9, 42.7, 39.4, 38.6, 37.3, 37.1, 36.6, 36.0, 34.0, 33.9, 30.9, 18.4, 18.1,

puriﬁed by ﬂash chromatography on silica gel (15−20% EtOAc/

hexanes) to aﬀord the desired product 77 as a colorless oil (2.5 mg,

2

0

0.0023 mmol, 45%, 95% brsm): [α] −18.30 (c 0.10, CH Cl ); IR

D

2

+

−1

7.5, 14.3, 13.7; HRMS (ES ) m/z (M + H) : calcd for C H O ,

(ﬁlm, cm ) 2956, 2927, 2867, 1725, 1467, 1380, 1263, 1147, 1090,

837, 740; H NMR (600 MHz, CDCl ) δ 6.95 (ddd, J = 15.0, 9.4, 5.1

37

59 12

1

95.4007; found, 695.4017.

Compound (−)-76. To a solution of 13.6 mg of the crude 74 in 7.0

3

Hz, 1 H), 6.26 (dd, J = 15.0, 10.9 Hz, 1 H), 6.04−5.93 (m, 2 H), 5.46

(dd, J = 15.0, 9.1 Hz, 1 H), 5.33−5.20 (m, 2 H), 4.89 (d, J = 2.8 Hz, 1

H), 4.27 (dd, J = 11.7, 4.2 Hz, 1 H), 4.03 (dd, J = 11.7, 5.0 Hz, 1 H),

3.98 (t, J = 9.2 Hz, 1 H), 3.88−3.71 (m, 3 H), 3.60−3.41 (m, 4 H),

3.45 (s, 3 H), 3.38−3.29 (m, 2 H), 2.49−2.27 (m, 7 H), 2.06−1.87

(m, 4 H), 1.75−1.16 (m, 14 H), 1.02 (d, J = 6.9 Hz, 3 H), 0.87−0.82

(m, 33 H), 0.12−0.09 (m, 9 H), 0.08 (s, 3 H), 0.03 (s, 3 H), −0.04 (s,

mL of THF at 0 °C was added solid K CO (7 mg). The resulting

2

3

solution was stirred at 0 °C for 7 h. The reaction was then quenched

with 10 mL of sat. aq. NH Cl at 0 °C. The resulting mixture was then

4

warmed to room temperature, and the organic phase was extracted

with CH Cl (3 × 30 mL). The combined organic layers were dried

with Na SO₄and concentrated in vacuo. The crude product was

2

Q

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

3

1

6

3

1

H); ¹³C NMR (125 MHz, CDCl ) δ 173.6, 165.8, 146.4, 140.5,

1.85 (m, 2 H), 1.74−1.68 (m, 1 H), 1.63−1.16 (m, 19 H), 1.03 (d, J =

3

1

3

30.3, 130.0, 125.0, 123.2, 83.0, 81.3, 73.9, 73.5, 73.3, 73.2, 72.8, 70.6,

8.8, 65.5, 58.9, 43.5, 39.7, 39.4, 38.1, 36.6, 36.4, 36.2, 35.1, 34.1, 33.5,

1.3, 27.1, 26.4, 26.23, 26.16, 22.4, 22.2, 18.82, 18.78, 18.5, 18.3, 18.2,

6.6 Hz, 3 H), 0.86 (t, J = 6.6 Hz, 3 H), 0.85 (d, J = 6.2 Hz, 3 H); C

NMR (125 MHz, CDCl , residual solvent peak set at 77.0 ppm) δ

3

173.5, 165.8, 146.6, 141.4, 131.0, 126.6, 123.6, 122.7, 93.9, 82.9, 80.8,

80.5, 74.0, 73.7, 72.8, 72.6, 72.3, 71.4, 67.9, 67.7, 65.1, 58.9, 42.7, 39.4,

38.6, 37.3, 37.1, 36.6, 34.1, 34.0, 33.9, 31.7, 30.9, 29.0, 28.9, 24.9, 22.6,

+

4.7, 13.9, 13.8, −2.8, −3.7, −4.0, −4.1, −5.0; HRMS (ES ) m/z (M +

+

Na) : calcd for C H O Si Na, 1073.6577; found, 1073.6556.

56

102 12

3

+

Compound (−)-78. To a solution of 77 (2.0 mg, 0.0019 mmol) in

18.1, 17.5, 14.3, 14.1; HRMS (ES ) m/z (M + Na) : calcd for

0.5 mL of THF in a polypropylene tube at 0 °C were added 0.5 mL of

C H O Na, 773.4452; found, 773.4452.

41

66 12

pyridine and 0.5 mL of HF·Pyridine complex (70% HF) dropwise via

Eppendorf pipet. The resulting solution was stirred at 0 °C for 5 min.

The cold bath was then removed, and the resulting solution was stirred

at room temperature for another 24 h. The reaction was then

Compound (−)-82a. To a solution of 76 (18.0 mg, 0.0186 mmol)

in 3.5 mL of CH Cl at room temperature were added sequentially a

2

solution of 2,3,5-collidine (34.5 mg/mL in CH Cl , 0.89 mL, 0.25

2

mmol) and a solution of the acid chloride 81 (21.5 mg/mL in CH Cl ,

2

quenched with 10 mL of sat. aq. NaHCO solution slowly and stirred

at room temperature for 30 min. The organic phase was extracted with

0.60 mL, 0.11 mmol) via syringe. The resulting mixture was stirred at

room temperature for 5.5 h. The solution was quenched with saturated

3

CH Cl (3 × 20 mL). The combined organic layers were dried with

aqueous NH Cl. The resulting mixture was extracted with EtOAc. The

2

4

Na SO and concentrated in vacuo. The crude product was puriﬁed by

combined organic layers were washed with brine, dried with Na SO ,

2

4

2

4

ﬂash chromatography on silica gel (2−4% MeOH/CH Cl ) to aﬀord

and concentrated in vacuo. The crude product was puriﬁed by ﬂash

chromatography on silica gel (15% EtOAc/hexanes) to aﬀord the

desired product 82a as a colorless oil (18.5 mg, 0.018 mmol, 95%):

[α]²⁰−23.48 (c 0.28, CH Cl ); IR (ﬁlm, cm ) 2928, 2855, 1746,

2

the desired product 78 as colorless amorphous solid (1.3 mg, 0.0018

mmol, 93%): [α]²⁰−53.16 (c 0.071, MeOH); IR (ﬁlm, cm ) 3421,

−1

D

−1

2

7

1

5

962, 2925, 2869, 1725, 1461, 1370, 1265, 1146, 1107, 1072, 1045,

40, 668; H NMR (600 MHz, CDCl , residual solvent peak set at

.24 ppm) δ 6.95 (ddd, J = 15.1, 10.0, 4.9 Hz, 1 H), 6.26 (dd, J = 14.9,

0.9 Hz, 1 H), 6.05 (t, J = 10.9 Hz, 1 H), 5.95 (d, J = 15.4 Hz, 1 H),

.44 (dd, J = 14.9, 9.8 Hz, 1 H), 5.35 (d, J = 11.6 Hz, 1 H), 5.27 (td, J

D

2

1

1726, 1658, 1463, 1361, 1254, 1155, 1124, 1095, 1047, 898, 868, 838,

3

1

778; H NMR (500 MHz, CDCl ) δ 6.96 (ddd, J = 15.1, 9.3, 5.4 Hz, 1

3

H), 6.26 (dd, J = 15.0, 10.9 Hz, 1 H), 6.06−5.92 (m, 2 H), 5.46 (dd, J

= 14.9, 9.1 Hz, 1 H), 5.34−5.18 (m, 2 H), 4.89 (d, J = 2.9 Hz, 1 H),

4.31 (dd, J = 11.7, 4.0 Hz, 1 H), 4.05 (dd, J = 11.7, 5.3 Hz, 1 H), 3.98

(t, J = 9.2 Hz, 1 H), 3.88−3.70 (m, 3 H), 3.61−3.39 (m, 4 H), 3.45 (s,

3 H), 3.38−3.29 (m, 2 H), 2.59−2.29 (m, 9 H), 2.06−1.87 (m, 5 H),

1.75−1.14 (m, 10 H), 1.01 (d, J = 6.9 Hz, 3 H), 0.96−0.82 (m, 30 H),

=

10.8, 5.4 Hz, 1 H), 5.02 (s, 1 H), 4.35 (dd, J = 11.9, 3.9 Hz, 1 H),

4

.06 (dd, J = 11.9, 4.3 Hz, 1 H), 3.98 (t, J = 9.7 Hz, 1 H), 3.86−3.79

(

2

m, 1 H), 3.71−3.59 (m, 3 H), 3.46 (s, 3 H), 3.43−3.28 (m, 5 H),

.59−2.49 (m, 2 H), 2.42−2.20 (m, 8 H), 2.07−1.97 (m, 2 H), 1.92−

.84 (m, 2 H), 1.74−1.67 (m, 1 H), 1.65−1.41 (m, 4 H), 1.36−1.15

1

3

1

0.13−0.09 (m, 9 H), 0.08 (s, 3 H), 0.03 (s, 3 H), −0.05 (s, 3 H);

C

(

m, 9 H), 1.03 (d, J = 6.9 Hz, 3 H), 0.89 (t, J = 7.3 Hz, 3 H), 0.85 (d, J

NMR (125 MHz, CDCl ) δ 171.5, 165.8, 146.6, 140.6, 130.3, 128.0,

3

=

6.6 Hz, 3 H); ¹³C NMR (125 MHz, CDCl , residual solvent peak set

125.0, 123.1, 82.9, 82.6, 81.3, 73.9, 73.5, 73.33, 73.28, 72.8, 70.6, 69.2,

68.7, 66.0, 58.9, 43.5, 39.7, 39.4, 38.1, 36.6, 36.4, 36.1, 33.5, 33.4, 31.3,

26.4, 26.23, 26.16, 18.83, 18.80, 18.5, 18.3, 18.2, 14.7, 14.4, −2.8, −3.7,

3

at 77.0 ppm) δ 173.5, 165.7, 146.6, 141.4, 131.0, 126.6, 123.6, 122.7,

9

5

2

3.9, 82.9, 80.8, 80.5, 74.0, 73.8, 72.8, 72.6, 72.3, 71.4, 67.9, 67.7, 65.1,

+

8.9, 42.7, 39.4, 38.6, 37.3, 37.1, 36.6, 34.0, 33.92, 33.86, 30.9, 27.0,

−4.0, −4.1, −5.0; HRMS (ES ) m/z (M + Na) : calcd for

+

2.2, 18.1, 17.5, 14.3, 13.7; HRMS (ES ) m/z (M + Na) : calcd for

C H O Si Na, 1069.6264; found, 1069.6271.

56

98 12

3

C H O Na, 731.3982; found, 731.3986.

Compound (−)-82. To a solution of 82a (11.4 mg, 0.0109 mmol)

38

60 12

(

−)-Mandelalide L (16). To a solution of 76 (3.0 mg, 0.0031 mmol)

in 2.0 mL of THF in a polypropylene tube at 0 °C were added 2.0 mL

of pyridine and 2.0 mL of HF·Pyridine complex (70% HF) dropwise

via Eppendorf pipet. The resulting solution was stirred at 0 °C for 5

min. The cold bath was then removed, and the resulting solution was

stirred at room temperature for another 28 h. The reaction was then

in 1.0 mL of CH Cl at room temperature were added sequentially a

2

solution of 2,3,5-collidine (11.0 mg/mL in CH Cl , 1.10 mL, 0.100

mmol) and a solution of octanoyl chloride (10.0 mg/mL in CH Cl ,

2

1.10 mL, 0.068 mmol) via syringe. The resulting mixture was stirred at

room temperature for 13 h. The solution was quenched with saturated

quenched with 30 mL of sat. aq. NaHCO solution slowly and stirred

3

aqueous NH Cl. The resulting mixture was extracted with EtOAc. The

at room temperature for 30 min. The organic phase was extracted with

4

combined organic layers were washed with brine, dried with Na SO ,

CH Cl (3 × 40 mL). The combined organic layers were dried with

2

4

2

and concentrated in vacuo. The crude product mixture was puriﬁed by

ﬂash chromatography on silica gel (20% EtOAc/hexanes) to aﬀord the

desired product contaminated with octanoic acid, which was used

directly in the global deprotection step.

To a solution of the above product mixture in 0.5 mL of THF in a

polypropylene tube at 0 °C were added 0.5 mL of pyridine and 0.5 mL

of HF·Pyridine complex (70% HF) dropwise via Eppendorf pipet. The

resulting solution was stirred at 0 °C for 5 min. The cold bath was

then removed, and the resulting solution was stirred at room

temperature for another 38 h. The reaction was then quenched with

Na SO and concentrated in vacuo. The crude product was puriﬁed by

2 4

ﬂash chromatography on silica gel (2−4% MeOH/CH Cl ) to aﬀord

2

the desired product 82 as colorless amorphous solid (6.9 mg, 0.0098

mmol, 90%): [α]²⁰−29.97 (c 0.25, MeOH); IR (ﬁlm, cm ) 3429,

−1

D

3307, 2920, 1723, 1658, 1453, 1370, 1264, 1158, 1100, 1045, 984,

814735; H NMR (600 MHz, CDCl , residual solvent peak set at 7.26

1

3

ppm) δ 6.97 (ddd, J = 15.2, 9.9, 5.1 Hz, 1 H), 6.28 (dd, J = 14.8, 11.0

Hz, 1 H), 6.06 (t, J = 10.9 Hz, 1 H), 5.97 (d, J = 15.9 Hz, 1 H), 5.46

(dd, J = 14.8, 9.9 Hz, 1 H), 5.38 (d, J = 12.0 Hz, 1 H), 5.29 (td, J =

10.8, 5.5 Hz, 1 H), 5.04 (s, 1 H), 4.40 (dd, J = 11.9, 3.9 Hz, 1 H), 4.10

(dd, J = 11.9, 4.4 Hz, 1 H), 4.00 (t, J = 9.2 Hz, 1 H), 3.87−3.81 (m, 1

H), 3.73−3.61 (m, 3 H), 3.47 (s, 3 H), 3.44−3.29 (m, 5 H), 2.70−2.25

(m, 12 H), 2.08−2.00 (m, 2 H), 1.98−1.86 (m, 3 H), 1.75−1.45 (m, 3

H), 1.28 (d, J = 6.3 Hz, 3 H), 1.26−1.16 (m, 4 H), 1.05 (d, J = 6.9 Hz,

2

0 mL of sat. aq. NaHCO₃solution slowly and stirred at room

temperature for 30 min. The organic phase was extracted with CH Cl₂

2

(

3 × 30 mL). The combined organic layers were dried with Na SO₄

2

and concentrated in vacuo. The crude product was puriﬁed by RP18

HPLC (10−90% MeCN−H O, 0.05% formic acid) to aﬀord the

3 H), 0.86 (d, J = 6.5 Hz, 3 H); ¹³C NMR (125 MHz, CDCl , residual

2

3

natural product 16 as a colorless amorphous solid (1.7 mg, 0.0023

solvent peak set at 77.16 ppm) δ 171.6, 165.9, 146.9, 141.6, 131.2,

126.9, 123.7, 122.8, 94.1, 83.1, 82.6, 80.9, 80.7, 74.1, 73.9, 73.0, 72.7,

72.4, 71.6, 69.2, 68.0, 67.7, 65.8, 59.1, 42.9, 39.6, 38.8, 37.5, 37.2, 36.7,

20

D

mmol, 75% over 2 steps): [α] −52.25 (c 0.07, MeOH); IR (ﬁlm,

−1

cm ) 3434, 2954, 2925, 2871, 1721, 1465, 1378, 1285, 1264, 1147,

1

+

1

109, 1069, 737; H NMR (600 MHz, CDCl , residual solvent peak

34.14, 34.06, 33.3, 31.04, 18.2, 17.6, 14.46, 14.45; HRMS (ES ) m/z

3

+

set at 7.24 ppm) δ 6.95 (ddd, J = 15.1, 10.4, 4.6 Hz, 1 H), 6.26 (dd, J =

4.7, 11.4 Hz, 1 H), 6.05 (t, J = 10.6 Hz, 1 H), 5.95 (d, J = 15.4 Hz, 1

H), 5.44 (dd, J = 14.7, 9.9 Hz, 1 H), 5.35 (d, J = 11.0 Hz, 1 H), 5.27

td, J = 10.5, 5.7 Hz, 1 H), 5.02 (s, 1 H), 4.35 (dd, J = 11.7, 3.7 Hz, 1

(M + Na) : calcd for C H O Na, 727.3669; found, 727.3719.

38

56 12

1

Compound (−)-84. Solid CuI (0.1 mg, 0.00043 mmol) was added

to a vial containing 82 (3.0 mg, 0.0043 mmol), and the vial was purged

(

with N gas, followed by addition of 0.25 mL of MeCN (degassed by

2

H), 4.06 (dd, J = 11.7, 4.0 Hz, 1 H), 3.98 (t, J = 9.9 Hz, 1 H), 3.86−

freeze−pump−thaw). To the resulting solution was added a solution

of N,N-diisopropylethylamine (3% v/v in MeCN, 0.050 mL, 0.0086

mmol), followed by a solution of the biotin-azide tag 83 (15.3 mg/mL

3

.79 (m, 1 H), 3.72−3.60 (m, 3 H), 3.46 (s, 3 H), 3.43−3.28 (m, 5 H),

.61−2.48 (m, 2 H), 2.43−2.21 (m, 8 H), 2.06−1.98 (m, 2 H), 1.92−

2

R

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

in MeCN, 0.20 mL, 0.0065 mmol). The obtained solution was stirred

ASSOCIATED CONTENT

Supporting Information

■

under N at room temperature for 18 h. The reaction mixture was then

2

*

S

loaded onto a silica gel column and puriﬁed by ﬂash chromatography

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.joc.8b00268.

1_H_N_M_R_a_n_d13_C_N_M_R_s_p_e_c_t_r_a_l_d_a_t_a_o_f_s_y_n_t_h_e_t_i_c

(

10−20% MeOH/CH Cl ) to aﬀord the desired product 84 as pale

2

20

yellow waxy solid (4.6 mg, 0.0039 mmol, 91%): [α] −11.19 (c 0.33,

MeOH); IR (ﬁlm, cm ) 3333, 2919, 2845, 1698, 1655, 1459, 1364,

1

solvent peak set at 4.78 ppm) δ 7.84−7.68 (m, 2 H), 6.85 (ddd, J =

1

D

−1

1

259, 1180, 1127, 1106, 1045; H NMR (600 MHz, CD OD, residual

3

compounds, concentration−response curves for bio-

logical assays (PDF )

5.1, 10.4, 4.2 Hz, 1 H), 6.14 (dd, J = 14.9, 10.9 Hz, 1 H), 5.91 (t, J =

0.9 Hz, 1 H), 5.81 (d, J = 16.1 Hz, 1 H), 5.35 (dd, J = 14.8, 9.8 Hz, 1

H), 5.24−5.11 (m, 2 H), 4.91 (s, 1 H), 4.39−4.32 (m, 2 H), 4.26 (dd,

J = 11.8, 3.7 Hz, 1 H), 4.18 (dd, J = 7.9, 4.4 Hz, 1 H), 3.95−3.85 (m, 2

H), 3.80−3.71 (m, 1 H), 3.63−3.04 (m, 26 H), 2.91−2.83 (m, 2 H),

AUTHOR INFORMATION

■

Corresponding Author

*smithab@sas.upenn.edu.

2

3

.81 (dd, J = 12.7, 5.0 Hz, 1 H), 2.64−2.56 (m, 3 H), 2.44−0.99 (m,

13

7 H), 0.94 (d, J = 6.9 Hz, 3 H), 0.75 (d, J = 6.5 Hz, 3 H); C NMR

ORCID

(

125 MHz, CD OD, residual solvent peak set at 49.00 ppm) δ 176.0,

3

Minh H. Nguyen: 0000-0003-3280-5375

Kerry L. McPhail: 0000-0003-2076-1002

Amos B. Smith III: 0000-0002-1712-8567

1

7

5

3

73.7, 167.7, 166.1, 148.9, 142.5, 131.8, 128.1, 125.9, 124.9, 123.6,

22.5, 96.3, 84.9, 82.7, 82.4, 75.0, 74.5, 74.3, 73.7, 73.4, 72.2, 71.6,

1.5, 71.30, 71.29, 70.1, 69.9, 69.2, 68.3, 66.7, 63.4, 61.6, 59.3, 57.0,

5.8, 44.2, 41.1, 40.9, 39.8, 38.7, 38.4, 37.8, 37.3, 36.9, 35.4, 35.0, 34.2,

Notes

+

2.1, 31.4, 30.4, 29.8, 29.5, 26.9, 21.8, 18.8, 18.0, 14.5; HRMS (ES )

+

The authors declare no competing ﬁnancial interest.

m/z (M + H) : calcd for C H N O S, 1177.6318; found,

5

8

93

6

17

1

177.6328.

Chemicals and Reagents for Biological Studies. All synthetic

ACKNOWLEDGMENTS

■

mandelalide compounds were reconstituted in cell culture grade

DMSO (100%) and stored at −20 °C until the day of treatment; ﬁnal

concentrations of DMSO never exceeded 0.1%. 3-(4,5-Dimethylth-

iazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) was from Sigma-

Aldrich Corp. (St. Louis, MO), and oligomycin A, from Santa Cruz

Biotechnology, Inc. (Dallas, TX). General cell culture supplies were

from Thermo Fisher Scientiﬁc (Waltham, MA) or Sigma-Aldrich.

Mammalian Cell Culture and Analysis of Cell Viability.

Human HeLa cervical cancer cells were from the American Type

Culture Collection (ATCC) and were grown in Minimal Essential

Medium Eagle (MEM) formulation (Mediatech Inc., Manassas, VA)

with 10% FBS, L-glutamine (2 mM), and 1% penicillin/streptomycin.

Financial support was provided by the NIH through Grant CA-

9033 and in part by GM-29028. T.K. thanks JSPS for a

Fellowship for Young Japanese Scientist. We also thank Drs.

George Furst and Jun Gu and Dr. Rakesh K. Kohli for

assistance obtaining NMR and high-resolution mass spectra,

respectively.

1

REFERENCES

■

(

1) For reviews, see: (a) Smith, A. B., III; Adams, C. M. Acc. Chem.

Res. 2004, 37, 365. (b) Smith, A. B., III; Wuest, W. M. Chem. Commun.

008, 5883.

2

^C^e^l^l^s^w^e^r^e^m^aⁱⁿ^t^aⁱⁿ^e^dⁱⁿ^a^h^u^mⁱ^dⁱ^ﬁ^e^d^c^h^a^m^b^e^r^a^t³⁷^°^C^wⁱ^t^h⁵^%^C^O2

(2) (a) Smith, A. B., III; Doughty, V. A.; Lin, Q.; Zhuang, L.;

McBriar, M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama,

K.; Sobukawa, M. Angew. Chem., Int. Ed. 2001, 40, 191. (b) Smith, A.

B., III; Lin, Q.; Doughty, V. A.; Zhuang, L.; McBriar, M. D.; Kerns, J.

K.; Brook, C. S.; Murase, N.; Nakayama, K. Angew. Chem., Int. Ed.

2001, 40, 196. (c) Smith, A. B., III; Sfouggatakis, C.; Risatti, C. A.;

Sperry, J. B.; Zhu, W.; Doughty, V. A.; Tomioka, T.; Gotchev, D. B.;

Bennett, C. S.; Sakamoto, S.; Atasoylu, O.; Shirakami, S.; Bauer, D.;

Takeuchi, M.; Koyanagi, J.; Sakamoto, Y. Tetrahedron 2009, 65, 6489.

(3) (a) Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am.

Chem. Soc. 1995, 117, 12011. (b) Smith, A. B., III; Beauchamp, T. J.;

LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.;

Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654.

and seeded at 10 000 cells/well 16−18 h before treatment. The

viability of cells was assessed by MTT assay after 72 h with the viability

of vehicle-treated cells at the end of the experiment deﬁned as 100%.

In all studies, concentrations were studied in triplicate and the activity

of 16, 75, 78, 82, and 84 was assessed relative to (−)-mandelalide A

(

5). Concentration−response relationships were analyzed using

nonlinear regression analysis ﬁt to a four-parameter logistic equation

with GraphPad Prism Software (GraphPad Software Inc., San Diego,

CA). EC₅₀± SE values for inhibition of HeLa Cell viability were

derived from at least three independent experiments (5, 16, 75, 78),

with the exception of 82 and 84 which were tested in parallel with 5

once (to 300 nM) in order to conserve material for advanced

biological studies.

(

4) (a) Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, 119,

925. (b) Smith, A. B., III; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.;

Sfouggatakis, C.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 14435.

c) Smith, A. B., III; Xian, M.; Kim, W.-S.; Kim, D.-S. J. Am. Chem. Soc.

6

Complex V Activity Assay. Mitochondrial ATPase activity was

measured with a MitoCheck Complex V activity assay kit (# 701000)

from Cayman Chemical (Ann Arbor, MI). Brieﬂy, the activity of

complex V in isolated bovine heart mitochondria was determined in a

colormetric assay by measuring the rate of NADH oxidation at 340 nm

(

2006, 128, 12368. (d) Smith, A. B., III; Xian, M. J. Am. Chem. Soc.

2006, 128, 66. (e) Sokolsky, A.; Smith, A. B., III. Org. Lett. 2012, 14,

4470. (f) Chen, M. Z.; Gutierrez, O.; Smith, A. B., III. Angew. Chem.,

(

captured every 30 s for 30 min) at 25 °C. The reaction rate was

Int. Ed. 2014, 53, 1279. (g) Farrell, M.; Melillo, B.; Smith, A. B., III.

Angew. Chem., Int. Ed. 2016, 55, 232. (h) Liu, Q.; Chen, Y.; Zhang, X.;

Houk, K. N.; Liang, Y.; Smith, A. B., III. J. Am. Chem. Soc. 2017, 139,

determined by plotting absorbance (y-axis), calculated from the slope

for the linear portion of each curve versus time (x-axis). Complex V

activity was calculated as % activity relative to the vehicle control:

8

710.

5) For recent examples, see: (a) Melillo, B.; Smith, A. B., III. Org.

Lett. 2013, 15, 2282. (b) Han, H.; Smith, A. B., III. Org. Lett. 2015, 17,

232. (c) Ai, Y.; Kozytska, M. V.; Zou, Y.; Khartulyari, A. S.; Smith, A.

(

⎡

rate of sample wells ⎤

complex V activity (%) =

_⎥× 100

⎢

⎣

rate of vehicle control ⎦

4

B., III. J. Am. Chem. Soc. 2015, 137, 15426. (d) Liu, Q.; Deng, Y.;

Smith, A. B., III. J. Am. Chem. Soc. 2017, 139, 13668.

(6) (a) Smith, A. B., III; Kim, W.-S. Proc. Natl. Acad. Sci. U. S. A.

2011, 108, 6787. (b) Smith, A. B., III; Han, H.; Kim, W.-S. Org. Lett.

2011, 13, 3328.

A concentration−response relationship was generated for (−)-man-

delalide A (5), on the day of the experiment, for comparison with ﬁxed

concentrations of 84 (1 μM) or a saturating concentration of

oligomycin A (12.5 μM).

S

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(

7) For a preliminary report of this work, see: Nguyen, M. H.;

Imanishi, M.; Kurogi, T.; Smith, A. B., III. J. Am. Chem. Soc. 2016, 138,

675.

8) (a) Newman, J. D.; Cragg, M. G. Mar. Drugs 2014, 12, 255.

b) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311. (c) Blunt,

(27) (a) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.;

Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori, R. J. Am. Chem. Soc.

1987, 109, 1596. (b) Burk, M. J.; Allen, J. G.; Kiesman, W. F. J. Am.

Chem. Soc. 1998, 120, 657.

(28) Hojo, M.; Ishibashi, N.; Ohsumi, K.; Miura, K.; Hosomi, A. J.

Organomet. Chem. 1994, 473, C1.

3

(

J. W.; Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.; Prinsep, M. R.

Nat. Prod. Rep. 2012, 29, 144. (d) Dalby, S. M.; Paterson, I. Curr. Opin.

Drug Discovery Dev. 2010, 13, 777. (e) Nicolaou, K. C.; Chen, J. S.;

Dalby, S. M. Bioorg. Med. Chem. 2009, 17, 2290. (f) Paterson, I.;

Anderson, E. A. Science 2005, 310, 451.

(29) (a) Trost, B. M.; Silverman, S. M.; Stambuli, J. P. J. Am. Chem.

Soc. 2011, 133, 19483. (b) Lee, T. V.; Channon, J. A.; Cregg, C.;

Porter, J. R.; Roden, F. S.; Yeoh, H. T. L. Tetrahedron 1989, 45, 5877.

(30) To the best of our knowledge, there have been no reports of

transition-metal-mediated reactions between allylsilanes and alkenyl

halides. The closest example is a Pd-catalyzed cross-coupling between

allylsilane and styryl bromide in 28% yield; see: Hatanaka, Y.; Hiyama,

T. J. Org. Chem. 1988 , 53 , 918.

(

9) Sikorska, J.; Hau, A. M.; Anklin, C.; Parker-Nance, S.; Davies-

Coleman, M. T.; Ishmael, J. E.; McPhail, K. L. J. Org. Chem. 2012, 77,

066.

10) (a) Willwacher, J.; Fu

217. (b) Willwacher, J.; Heggen, B.; Wirtz, C.; Thiel, W.; Fu

Chem. - Eur. J. 2015, 21, 10416.

11) Lei, H.; Yan, J.; Yu, J.; Liu, Y.; Wang, Z.; Xu, Z.; Ye, T. Angew.

Chem., Int. Ed. 2014, 53, 6533.

12) Computational tools were used to support revised absolute

6

(

4

̈

rstner, A. Angew. Chem., Int. Ed. 2014, 53,

rstner, A.

(

31) See Supporting Information.

32) (a) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173. (b) Li,

̈

P.; Li, J.; Arikan, F.; Ahlbrecht, W.; Dieckmann, M.; Menche, D. J. Org.

Chem. 2010, 75, 2429.

(

(33) Xiao, X.; Bai, D. Synlett 2001, 2001, 535.

(

(34) Hanessian, S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. J. Am. Chem.

structures of mandelalides B−D; see: Snyder, K. M.; Sikorska, J.; Ye,

T.; Fang, L.; Su, W.; Carter, R. G.; McPhail, K. L.; Cheong, P. H. Org.

Biomol. Chem. 2016, 14, 5826.

Soc. 1990, 112, 5276.

35) Meiries, S.; Bartoli, A.; Decostanzi, M.; Parrain, J.; Commeiras,

L. Org. Biomol. Chem. 2013, 11, 4882.

36) Plummer, C. W.; Soheili, A.; Leighton, J. L. Org. Lett. 2012, 14,

462.

37) Lebel, H.; Paquet, V. J. Am. Chem. Soc. 2004, 126, 320.

38) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett

998, 1998, 26.

39) Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T. J.;

(

13) (a) Bru

2, 1292. (b) Veerasamy, N.; Ghosh, A.; Li, J.; Watanabe, K.; Serrill, J.

D.; Ishmael, J. E.; McPhail, K. L.; Carter, R. G. J. Am. Chem. Soc. 2016,

38, 770. For synthetic studies of mandelalide A aglycon, see:

c) Reddy, K. M.; Yamini, V.; Singarapu, K. K.; Ghosh, S. Org. Lett.

014, 16, 2658. (d) AnkiReddy, P.; AnkiReddy, S.; Sabitha, G.

ChemistrySelect 2017, 2, 1032.

14) Nazari, M.; Serrill, J. D.; Sikorska, J.; Ye, T.; Ishmael, J. E.;

McPhail, K. L. Org. Lett. 2016, 18, 1374.

15) Nazari, M.; Serrill, J. D.; Wan, X.; Nguyen, M. H.; Anklin, C.;

̈

tsch, T. M.; Bucher, P.; Altmann, K. Chem. - Eur. J. 2016,

(

2

(

2

1

(

́

(

1

(

2

Stahl, W.; Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A. L.;

Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115, 7593.

(

40) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.

Bull. Chem. Soc. Jpn. 1979, 52, 1989.

41) (a) Bhatt, U.; Christmann, M.; Quitschalle, M.; Claus, E.;

(

Gallegos, D. A.; Smith, A. B., III.; Ishmael, J. E.; McPhail, K. L. J. Med.

Chem. 2017, 60, 7850.

(

Haslett, G. W. Org. Lett. 2013, 15, 1338. (b) Hwang, S.; Baek, I.; Lee,

C. Org. Lett. 2016, 18, 2154. (c) Watanabe, K.; Li, J.; Veerasamy, N.;

Ghosh, A.; Carter, R. G. Org. Lett. 2016, 18, 1744.

(

Kalesse, M. J. Org. Chem. 2001, 66, 1885. (b) Jagel, J.; Maier, M. E.

Synthesis 2009, 2009, 2881. A similar approach employing

intramolecular Heck reaction was reported in ref 12c.

(42) Kahne, D.; Walker, S.; Cheng, Y.; VanEngen, D. J. Am. Chem.

Soc. 1989, 111, 6881.

16) Winder, P. L. Ph.D. Thesis, Florida Atlantic University, 2009.

17) For synthetic studies toward madeirolide A, see: (a) Paterson, I.;

(43) A minor amount of 79 (<10%) was obtained during the ester

saponiﬁcation of 74.

(

18) (a) Smith, A. B., III; Kim, W.-S.; Tong, R. Org. Lett. 2010, 12,

5

88. (b) Smith, A. B., III; Hoye, A. T.; Martinez-Solorio, D.; Kim, W.-

(44) Stewart, S. G.; Braun, C. J.; Polomska, M. E.; Karimi, M.;

Abraham, L. J.; Stubbs, K. A. Org. Biomol. Chem. 2010, 8, 4059.

(45) (a) Huisgen, R. Angew. Chem. 1963, 75, 604. (b) Rostovtsev, V.

V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.

2002, 41, 2596.

S.; Tong, R. J. Am. Chem. Soc. 2012, 134, 4533. (c) Martinez-Solorio,

D.; Hoye, A. T.; Nguyen, M. H.; Smith, A. B., III. Org. Lett. 2013, 15,

2454. (d) Nguyen, M. H.; Smith, A. B., III. Org. Lett. 2013, 15, 4258.

(e) Nguyen, M. H.; Smith, A. B., III. Org. Lett. 2014, 16, 2070.

(f) Nguyen, M. H.; Smith, A. B., III. Org. Lett. 2013, 15, 4872.

(g) Martinez-Solorio, D.; Melillo, B.; Sanchez, L.; Liang, Y.; Lam, E.;

Houk, K. N.; Smith, A. B., III. J. Am. Chem. Soc. 2016, 138, 1836.

h) Nguyen, M. H.; O’Brien, K. T.; Smith, A. B., III. J. Org. Chem.

017, 82, 11056.

19) Matsuda, I.; Fukuta, Y.; Tsuchihashi, T.; Nagashima, H.; Itoh, K.

Organometallics 1997, 16, 4327.

(

2

(

20) Sadhu, K. M.; Matteson, D. S. Tetrahedron Lett. 1986, 27, 795.

(

21) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;

Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.

Chem. Soc. 2002, 124, 1307.

(

22) (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J.

Am. Chem. Soc. 1990, 112, 2801. (b) Jacobsen, E. N.; Zhang, W.; Muci,

A. R.; Ecker, J. R.; Deng, Li. J. Am. Chem. Soc. 1991, 113, 7063.

(

23) Nicolaou, K. C.; Lysenko, Z. Tetrahedron Lett. 1977, 18, 1257.

24) (a) Donohoe, T. J.; Butterworth, S. Angew. Chem., Int. Ed. 2005,

44, 4766. (b) Donohoe, T. J.; Wheelhouse, K. M. P.; Lindsay-Scott, P.

J.; Churchill, G. H.; Connolly, M. J.; Butterworth, S.; Glossop, P. A.

Chem. - Asian J. 2009, 4, 1237. (c) Pilgrim, B. S.; Donohoe, T. J. J. Org.

Chem. 2013, 78, 2149 and references cited therein.

(

1

(

25) Cheng, H.; Stark, C. B. W. Angew. Chem., Int. Ed. 2010, 49,

587.

26) Walba, D. M.; Stoudt, G. S. Tetrahedron Lett. 1982, 23, 727.

T

DOI: 10.1021/acs.joc.8b00268

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Synthetic Access to the Mandelalide Family of Macrolides: Development of an Anion Relay Chemistry Strategy

DOI: 10.1021/acs.joc.8b00268

Source and publish data:

Authors:

Article abstract of DOI:10.1021/acs.joc.8b00268

Full text of DOI:10.1021/acs.joc.8b00268

Products guided by the article

R&D Labs maybe for 103233-25-6

Relevant to this article

Hot Product