Synthesis of Rhamnolipid Derivatives Containing Ester Isosteres

hydroxy-fatty acids of various chain lengths (Figure 1 ). More

Letter

Synthesis of Rhamnolipid Derivatives Containing Ester Isosteres

Lei Wang and Todd L. Lowary*

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sı Supporting Information

ABSTRACT: Rhamnolipids are biosurfactants with many appli-

cations, arising from their inherent biological activity and their

potential as bioremediation agents. Herein, we report the synthesis

of four rhamnolipid derivatives in which the ester linkage

connecting the two lipid chains in the natural compound is

replaced with amide, ketone, ether, or hydrocarbon functional groups. Such compounds are anticipated to have enhanced hydrolytic

stability and thus be useful probes of rhamnolipid-mediated biology and biotechnology.

hamnolipids (RLs), which are a family of amphiphilic

glycolipids produced by Pseudomonas aeruginosa, possess

A key structural feature of dilipid RLs is the ester bond that

connects the two fatty acyl groups. Compared to other

functional groups, esters are relatively unstable and are

susceptible to esterase cleavage in biological systems. Replacing

the ester functionality with isosteric groups can often improve

metabolic stability and result in retained or improved

a host of biological functions, including bioﬁlm regulation,

immune modulation, antimicrobial eﬀects, and anticancer

activity. The biosurfactant ability of these compounds has

led to their potential use as bioremediation agents for organic

and heavy-metal contaminated sites. RLs consist of one or

biological activities. In this paper, we describe the ﬁrst

stereoselective synthesis of four dilipid RL derivatives (Figure

two rhamnopyranose (Rhap) monosaccharides attached to a

lipid containing one (monolipid), or usually two (dilipid), C3-

) in which the ester bond is replaced with other groups

including amide (1), ether (2), hydrocarbon (3), and ketone

4) functionalities. We envisioned that these compounds

(

would be powerful probes for understanding the biological and

biotechnological roles of RLs.

The retrosynthetic analysis of 1−4 is outlined in Scheme 1.

Disconnection of the glycosidic bond in 1−4 gives rise to

glycosyl donor 5 and alcohols 6−9. Hydroxy-amide 6 could be

obtained via the coupling of β-amino ester 10 and the β-

hydroxy acid obtained from 11. The synthesis of hydroxy-ether

could begin with displacement of the iodide 12 with the β-

hydroxy ester obtained from 11. For the preparation of 3, we

envisioned hydrogenation of alkene 8, which could be

generated by a Wittig reaction between aldehyde 13 and a

triphenylphosphonium ylide produced from iodide 12. Finally,

ketone 4 could be generated by glycosylation of 9 with 5,

followed by lactone cleavage and oxidation of the resulting

hydroxyl group. Access to 9 could be achieved by

regioselective β-hydroxylation of 8 and in situ lactonization.

With this plan in place, we moved forward on accessing the

targets. The synthesis of glycosyl imidate 5 is described in

Scheme S1 in the Supporting Information. Discussed below is

Figure 1. Structures of the naturally occurring RLs and the four

dilipid RL derivatives synthesized in this paper.

than 100 RL homologues or congeners have been identiﬁed,

but the structural features in these molecules required for their

biological activity, or their ability to act as bioremediation

agents, are not well understood.

Despite their biological and biotechnological importance,

relatively little work on the chemical synthesis of RLs, either

those present in nature or their derivatives, has been reported.

Received: November 4, 2020

The ﬁrst synthesis of RLs, pioneered by van Boom and co-

d,f

workers, was expanded to a library of these molecules by

Rademann. Recently, Pemberton and co-workers reported a

4b,e

scalable method to synthesize a monolipid RL library.

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 1. Retrosynthetic Analysis of RL Derivatives 1−4

Scheme 2. Synthesis of (A) β-Hydroxy Carboxylic Acid 16

and (B) Amide-Linked Dilipid RL Analogue 1

the preparation of building blocks 6−9 and their elaboration

into 1−4.

We ﬁrst addressed the synthesis of the amide-linked

compound 1 (Scheme 2). The key intermediate to access

this target is amide 6, which we prepared from 10 and 11. The

synthesis of 11 (Scheme 2A) was achieved via the hydro-

genation of β-ketoester 14, using Noyori’s catalyst (Ru-(R)-

BINAP). This reaction produced the enantiomerically pure β-

hydroxy ester 15 in 88% yield and 92% enantiomeric excess

(

ee). Determination of the ee was achieved by coupling the

hydroxyl group of 15 with (S)-(+)-O-acetylmandelic acid and

inspection of the H NMR spectrum. Protection of 15 to give

With key intermediate 6 in hand, it was converted to the

target compound in three steps. First, TMSOTf-promoted

glycosylation of 6 with trichloroacetimidate 5 gave a 3:1 α:β

mixture of protected RLs. After puriﬁcation, the α-RL 21 was

1 was performed in 92% yield by reaction with tert-

butyldimethylsilyl chloride (TBSCl) and silver nitrate

AgNO ) in pyridine and tetrahydrofuran (THF). Saponiﬁca-

(

tion of methyl ester 11 proceeded in 90% yield upon treatment

with lithium hydroxide monohydrate to aﬀord carboxylic acid

obtained in 62% yield. The one-bond C−H coupling constant

( J

) was used to assign the α- and β-isomers. The value

C‑1,H‑1

6, which was needed for subsequent amidation steps (see

for the major product was 170.2 Hz, indicating the α-

stereochemistry. Two deprotection steps, ester hydrolysis and

description below).

Compound 10 was synthesized (Scheme 2B) starting from a

Horner−Wadsworth−Emmons reaction between heptanal and

the commercially available C-phosphonate 17, providing E-

alkene 18 in 82% yield. Subsequent 1,4-addition of lithium

hydrogenolysis, led to the formation of the amide-linked RL

analogue 1 in 76% yield.

We next turned our attention to the synthesis of the ether-

linked analogue 2 (Scheme 3). The route started with the

reduction of ester 11 to aﬀord primary alcohol 23 in 65% yield;

a product lacking the TBS group was also formed as a side

product. Treatment of 23 with iodine, triphenylphosphine

(R)-N-benzyl-N-phenylethylamide to 18 aﬀorded 19 in 86%

yield and 95% de. The R stereochemistry in the product was

assumed based on previous reports. The de was determined as

described below. Hydrogenolysis of 19 (at 60 psi) led to

cleavage of the N-benzyl and N-phenylethyl groups, providing

a 92% yield of the corresponding (R)-β-amino ester 10. A

portion of 10 was N-tosylated and chiral HPLC (see the

Supporting Information) was used to determine the de of the

product, which was assumed to be unchanged from 19. Amine

(PPh ), and imidazole resulted in its conversion, in 91% yield,

into iodide 12. To generate the dialkyl ether linkage, we ﬁrst

explored using NaH to alkylate 15 with 12. However, alcohol

15 decomposed under these conditions. We therefore next

investigated silver(I) oxide-assisted O-alkylation of 15 with 12.

A major side product in this reaction was dimerization of 12,

which presumably arose from the hydrolysis of 12 and

displacement of the iodide by the resulting alcohol to form

the ether. The yield of the desired product 24 was only 32%;

however, all attempts to improve it, including rigorous drying

of the solvent, were unsuccessful. Removal of the TBS

protecting group under acidic conditions proceeded in 91%

0 was then coupled with acid 16 by treatment with 2-(1H-

benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaﬂuorophos-

phate (HBTU) and N,N-diisopropylethylamine (DIEA) to

give amide 20 in 66% yield. Exposure of 20 to 1.5% HCl in

methanol led to the removal of silyl ether, aﬀording alcohol 6

in 92% yield.

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 3. Synthesis of Ether-Linked Dilipid RL Analogue 2

dinone (28), prepared from n-octanoyl chloride and 4-(S)-

benzyloxazolidinone 27, was treated with lithium hexame-

thyldisilazide (LiHMDS) and benzyl 2-bromoacetate to aﬀord

9 in 76% yield. The stereochemistry of the newly formed

stereocenter was assumed based on the stereochemical model

for this auxiliary. Removal of the oxazolidinone with LiOH in

the presence of 30% H O gave the chiral carboxylic acid 30 in

5% yield. The acid moiety of 30 was then chemoselectively

reduced with BH ·Me S in THF to aﬀord, in 90% yield,

alcohol 31.

The next step was to oxidize alcohol 31 to form the

corresponding aldehyde 13. Initially, a Swern oxidation was

used for this purpose. However, the value of the optical

rotation for the product was zero, suggesting that the

stereogeneic center at the α-position had racemized during

the oxidation. To conﬁrm that 13 was a mixture of two

compounds, it was reacted with (2S, 4S)-(+)-pentanediol and

p-toluenesulfonic acid to generate an acetal from the aldehyde

(

see Scheme S2 in the Supporting Information). The crude

yield to give alcohol 7. TMSOTf-mediated glycosylation of 7

with donor 5 aﬀorded a 3.5:1 α:β mixture of protected RLs.

H NMR spectrum of this product showed two diastereomers

in a 1:1 ratio, indicating that racemization of 13 had indeed

occurred during oxidation. This racemization was presumably

caused by the base used during the Swern oxidation. To

prevent racemization, the less-basic Ley−Griﬃth oxidation,

which involves tetrapropylammonium perruthenate (TPAP)

and the co-oxidant N-methyl morpholine oxide (NMO), was

The desired α-RL (25) was obtained in 66% yield and the α-

stereochemistry of 25 was determined by the J

value

C‑1,H‑1

(

168.9 Hz). After saponiﬁcation and hydrogenolysis, the ether

linked target 2 was obtained in 72% yield over the two steps.

The synthesis of hydrocarbon RL analogue 3 is shown in

Scheme 4. A key transformation in this route is the Wittig

reaction between the enantiopure α-alkyl aldehyde 13 and the

triphenylphosphonium ylide produced from 32 to obtain Z-

alkene 33. Therefore, implementation of this approach ﬁrst

required the synthesis of 13 and 32.

used to oxidize 31 to 13. The crude H NMR spectrum of the

acetal produced from the reaction between 13 and (2S, 4S)-

(

+)-pentanediol showed only one diastereomer, indicating that

no epimerization had occurred during this oxidation.

Having prepared aldehyde 13, a phosphonium salt 32 was

generated from iodide 12, using triphenylphosphine in toluene

To prepare 13, we employed the Evans asymmetric

alkylation method. Thus, (S)-N-n-octanoyl-4-benzyloxazoli-

with Hunig’s base. The phosphonium ylide was produced by

reaction of LiHMDS in hexamethylphosphoramide (HMPA)/

THF with 32. After the addition of 13, the Z-alkene 33 was

isolated in 67% yield; none of the E-alkene was isolated. The

Scheme 4. Synthesis of Hydrocarbon Dilipid RL Analogue 3

stereochemistry was conﬁrmed by the J value between the two

alkene hydrogens, which was 10.5 Hz. After deprotection of

the silyl ether using HCl in methanol (90% yield), the resulting

alcohol 8 was glycosylated with 5 to aﬀord a 3.5:1 mixture of

protected RLs. Puriﬁcation provided the desired α-RL 34 in

4% yield; the α-stereochemistry was conﬁrmed by the J

C‑1,H‑1

value (168.8 Hz). Treatment of 34 with hydrogen and Pd/C

led to reduction of the double bond and removal of all of the

benzyl groups to generate the hydrocarbon analogue 3 in 86%

yield.

To prepare the ketone analogue 4, alkene 8, which was used

for the synthesis of hydrocarbon analogues, could also be

employed. As shown in Scheme 5A, we reasoned that if 8

could be converted to a 1,3-diol (e.g., 36), the newly formed

hydroxyl group would be automatically protected through the

formation of a six-membered ring lactone ((S)-9 or (R)-9). To

explore this possibility, we used an approach reported by Li

and Roush, who developed an intramolecular hydrosilylation

method for the synthesis of β,δ-unsaturated alcohols using

Karstedt’s catalyst (Pt ((CH ) SiCHCH ) O ). First,

alcohol 8 was silylated and then by using 0.5 mol % Karstedt’s

catalyst in toluene, an intramolecular C−Si bond formation

process led to the formation of 35. Subsequent oxidation of the

C−Si bond under basic conditions resulted in the formation of

lactones (S)-9 and (R)-9 in a combined 75% yield.

NOESY was used to assign the stereochemistry of the newly

formed stereocenter in these lactones. As shown in Scheme 5B,

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

The Supporting Information is available free of charge at

Letter

Scheme 5. (A) Intramolecular Hydrosilylation−Lactone

Formation Sequence on 8, Using Karstedt’s Catalyst; (B)

Use of NOESY To Conﬁrm the Newly Formed

Stereocenters of (S)-9 and (R)-9; and (C) Synthesis of

Ketone Dilipid RL Analogue 4

39. The saponiﬁcation/oxidation procedures on both (S)-9

and (R)-9 proceeded in essentially identical yields (∼70%).

The material obtained from the reactions leading to both 37

and 38 was combined and carried forward. After global

deprotection by Pd/C-catalyzed hydrogenolysis, the ketone

analogue 4 was produced in 81% yield.

In summary, an eﬃcient convergent strategy was developed

for the synthesis of four RL analogues (1−4) in which the ester

linkage connecting the two fatty acids was replaced with more

hydrolytically stable groups. The general approach to the

targets involved the formation of an acceptor (6−9), its

glycosylation with donor 5, and then deprotection of the

resulting product. To prepare the amide linked derivative 1,

the key step was an enantioselective 1,4-addition to α:β

unsaturated ester 18, which provided the (R)-β-amino ester

0. Subsequent amidation of 10 with a β-hydroxy-acid and

TBS deprotection gave 6. The key step in the synthesis of the

ether analogue 2 was a silver(I) oxide assisted O-alkylation of

β-hydroxy-ester 15, which successfully provided 7. The

synthesis of the hydrocarbon 3 and ketone 4 analogues share

the same key intermediate 8, which could be generated via a

Wittig reaction, using an aldehyde 13 produced from a Ley−

Griﬃth oxidation. Glycosylation of 8 and hydrogenation led to

. For the ketone analogue 4, we adopted a one-pot four-step

reaction sequence starting from 8, involving silyl ether

formation, hydrosilylation, oxidative cleavage, and lactone

formation, to provide lactone alcohols (S)-9 and (R)-9.

Glycosylation, lactone ring opening, and the late-stage Ley−

Griﬃth oxidation provided the ketone-containing target 4. The

use of these compounds as probes of RL-mediated biology is

ongoing.

ASSOCIATED CONTENT

sı Supporting Information

■

https://pubs.acs.org/doi/10.1021/acs.orglett.0c03670.

Experimental procedures, characterization data, and H

and C NMR spectra for all new compounds (PDF)

FAIR data, including the primary NMR FID ﬁles, for

compounds 1 −4 , 6−13, 15, 16, 18−26, 28−31, 33, 34,

and 37−39 (ZIP )

we assumed that the six-membered ring in (S)-9 and (R)-9

prefer chair conformations. A NOESY experiment of (R)-9

showed no correlation between H (δ 4.68 ppm) and H (δ

.04 ppm). However, a strong interaction was observed

between H and the CH group (δ 1.41 ppm) of the n-hexyl

AUTHOR INFORMATION

Corresponding Author

group. These results suggest that, in this compound, H and H

■

are trans to each other and that the newly formed stereocenter

is R. A NOESY experiment of (S)-9 showed strong interaction

Todd L. Lowary − Department of Chemistry, University of

Alberta, Edmonton, AB T6G 2G2, Canada; orcid.org/

between H (δ 4.50 ppm) and H (δ 1.95 ppm), which

indicated that this stereocenter has the opposite (S) stereo-

chemistry. As outlined below, these two lactones could be

separated and both could be used in accessing the products. An

advantage of this reaction sequence is that the newly formed

hydroxyl group can be automatically protected via lactone

formation. The other hydroxyl group remains free and can be

glycosylated (see Scheme 5C).

000-0002-8331-8211 ; Email: tlowary@ualberta.ca

Author

Lei Wang − Department of Chemistry, University of Alberta,

Edmonton, AB T6G 2G2, Canada

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.0c03670

Once the lactones (S)-9 and (R)-9 were produced,

TMSOTf-promoted glycosylation between 5 and acceptor

Notes

(

S)-9 aﬀorded a 4:1 mixture of protected RLs. The α-RL 37

The authors declare no competing ﬁnancial interest.

was puriﬁed in 63% yield; the J

value (168.4 Hz)

C‑1,H‑1

conﬁrmed the α-stereochemistry. Alternatively, the diaster-

eomer 38 was formed in 64% yield via glycosylation between 5

and acceptor (R)-9. After opening the lactones in (S)-9 and

ACKNOWLEDGMENTS

■

This work was supported by the Natural Sciences and

Engineering Research Council of Canada, the Alberta

Glycomics Centre, and the Canadian Glycomics Network.

(

R)-9 using LiOH in THF and water, the free hydroxyl groups

could be oxidized by the Ley−Griﬃth reagent to aﬀord ketone

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

4 , 1131 −1139. (b) Zhang, J.-X.; Labaree, D. C.; Hochberg, R. B.

Letter

W.L. thanks Alberta Innovates Technology Futures for a

studentship award. We thank the technical support staﬀ

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