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Synthesis of (+)/() pentenomycins via Me2 AlCl induced cascade reaction

Bejugam Santhosh Kumar, Girija Prasad Mishra, Batchu Venkateswara Rao⇑

Organic and Biomolecular Chemistry Division, CSIR—Indian Institute of Chemical Technology, Hyderabad 500607, India

a r t i c l e i n f o

 Article history:

Received 6 November 2012

Revised 19 March 2013

Accepted 22 March 2013Available online 3 April 2013

Keywords:

Carbocyclitols

Pentenomycins

Tebbe reaction

Me2AlCl reaction

a b s t r a c t

An efficient approach for the synthesis of (+) pentenomycin and () pentenomycin from D-ribose and

D-mannose, respectively, is described using Tebbe olefination of lactones 9 and 7 followed by Me2AlCl

induced disfavoured 5-(enol-endo)-exo-trig cyclization.

2013 Elsevier Ltd. All rights reserved.

Carbocyclitols are part structures of many interesting biologi-

cally active compounds.1 These molecules inhibit glycosidases

and show interesting biological activity such as anti-diabetic,

anti-HIV, andanti-cancer.2 Conversion of readily available carbohy-

drates into highly oxygenated carbocycles is an attractive routeadopted by many synthetic chemists,2–6 since this approach gives

the target compounds with high optical purity. Among the re-

ported methods, Ferrier rearrangement is considered as useful

transformation for the synthesis of cyclohexitols from 5-enopyr-

anosides.7 Later, Sinay and co-workers also developed a methodol-

ogy for the cyclohexitols from the 5-enohexopyranosides using

TIBAL.8 However, these methods failed to give cyclopentitols from

corresponding 4-enofuranosides, since they have to undergo unfa-

vorable 5-(enol-endo)-exo-trig cyclization.9

However, recently we developed a Tebbe-mediated cascade

reaction for the synthesis of cyclopentitols 4 and   5 from five-

membered sugar lactone 3 via 5-(enol-endo)-exo-trig cyclization

(Scheme 1), which is considered as a disfavored reaction according

to Baldwin rules.10 Herein we would like to present our observa-

tions while applying this cascade method for the synthesis ()

and (+) pentenomycins 1 and 2 (Fig. 1).

() Pentenomycin 1 belongs to the pentenomycin group of anti-

biotics and was isolated by Umino et al.11 from  Streptomyces

eurythermus, which exhibits activity against both Gram positive

and Gram negative bacteria. In view of its complex structure

and important biological activities, several synthetic approaches

for pentenomycins have been reported for racemic12 as well as

enantiopure forms.13

The retrosynthesis for 1 and 2 (Scheme 2) was envisaged based

on our Tebbe-mediated cascade method as shown in Scheme 2.

Oxidative cleavage of the double bond followed by 1,2 elimination

of water molecule in the proposed intermediates 6 and 8 should

give pentenomycins 1 and 2. The compounds 6 and 8 in turn canbe obtained by treating the lactones 7 and 9, respectively, with

Tebbe reagent.14,15 The lactones 7 and 9 can be synthesized from

the commercially available D-mannose and D-ribose, respectively.

For the synthesis of (+) pentenomycin 2 (Scheme 3), D-ribose

was converted into compound 10 in three steps using the reported

procedure.13f,16 Treatment of 10 with NaOH followed by chopping

the diol with NaIO4 afforded compound 11 in 80% yield. Refluxing

compound 11 in the presence of catalytic amount of PPTS in 2-pro-

panol furnished compound 7 required for the cascade reaction in

84% yield. When compound 7 was treated with Tebbe reagent

(1.8 equiv), the expected cascade reaction did not proceed, instead,

olefination of lactone took place to give the enol ether 13 in 78%

yield. Attempts to progress the cascade reaction by adding excess

Tebbe reagent (4 equiv) at 0 C, at rt or at reflux are unsuccessful.

In order to know whether free hydroxy group a to the lactone

obstructs further reaction by complexing with the Tebbe reagent,

the free hydroxy group was converted into TBS protected ether

to give 12. Treatment of compound 12 with Tebbe reagent also

failed to give the desired transformation and culminated at olefin

stage giving 14. From the above experiment, it was concluded that

the quaternary center adjacent to the enol ether in 13 and 14 may

be preventing the molecule to undergo further transformation.

At this stage, it was decided to screen various Lewis-acids17

(Table 1) for the transformation of 13 into carbocycle. Different

Lewis-acids such as BF3OEt2, TiCl4, SnCl4 in DCM and ZnCl2 in

THF/H2O18 were tried on 13 and none of them gave the required

product and every time decomposition occurred and we failed to

0040-4039/$ - see front matter 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetlet.2013.03.092

⇑ Corresponding author. Tel./fax: +91 40 27193003.

E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).

Tetrahedron Letters 54 (2013) 2845–2848

Contents lists available at SciVerse ScienceDirect 

Tetrahedro n Letters

j o u r n a l h o m e p a g e :   w w w . e l s e v i e r . c o m / l o c a t e / t e t l e t

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O O

O

O O

HO

O   O

HO

O

HO OH

HOOH

HO OH

HOOH

O

O   O

O   O   O

O   O

O

H  LA

O

LA

methylation

Tebbe reagent

cleavage of 

isopropylgroup

3

4

5

intramolecular 

aldol reaction

HH

methylation

Tebbe reagent

4-enofuranoside

Scheme 1. Tebbe-mediated cascade approach for the synthesis of cyclopentitols.

O

HO OHOH

O

HO OHOH

1 2

(-) pentenomycin   (+) pentenomycin

Figure 1. Structures of pentenomycins.

O

HO   OH

OH

O   O

HO

OH

O

O O

OO

OH D-mannose

(-) pentenomycin

O

HO OH

OH

O   O

HO

OH

O

O O

O O

OH  D-ribose

(+) pentenomycin

1 6 7

2   8   9

Tebbe

mediatedcascade

Tebbe

mediatedcascade

Scheme 2. Retrosynthesis of compounds 1 and 2.

O

O O

HO  O

OH

O

O O

HO   O

OH

O

O O

O   O

OR

O

O O

O

OR

O O

O

OH

HO OH

O

OH

a   b   d

e

7 R=H

12 R=TBS1011

15

2

13 R=H

14 R=TBS

c

f 

Scheme 3. Synthesis of (+) pentenomycin 2. Reagents and conditions: (a) (i) NaOH, H2O, 40 C, 20 min, (ii) NaIO4, 0 C, BaCl2, 30 min; 80%; (b) 2-propanol, PPTS (cat.), reflux,

80 C, 1.5 h, 84%; (c) TBS-Cl, imidazole, DCM, DMAP (cat.) 1 h, 85%; (d) Tebbe reagent (1.8 equiv), THF, 0C, 1 h, 78%; (e) Me2AlCl (1.2 equiv),  78 C, 20 min, 70%; (f)Amberlyst-15 in THF/H2O (2:1), 70 C, 5 h, 75%.

 Table 1List of Lewis-acids

Entry Reagent (equiv) Conditions Yield (15)

1 BF3OEt2 (1.2) DCM 0 C, 30 min Decomposition

2 TiCl4 (1.2) DCM 0 C–rt, 1 h Decomposition

3 SnCl4 (1.2) DCM 0 C–rt, 1 h Decomposition

4 ZnCl2 (1.2) THF/H2O, 0 C–rt, 7 h Decomposition

5 Me2AlCl (1.2) DCM, 78 C, 20 min 70% yield

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isolate any product in pure form. Then it was thought to use

Me2AlCl for this transformation, since it is known for its

exceptional 1,3 chelating ability19 and also aluminum-mediated

transformation of vinyl acetal to tetrahydropyrans was well

established in the literature which is popularly known as the

Petasis–Ferrier rearrangement.20,21

When enol ether 13 was subjected to Me2AlCl at 78 C in DCM,

interestingly it resulted directly in compound15

in 70% yield.{mp 61–64 C,   ½a20D   ¼ 19:0 (c = 1.0, CHCl3), lit.:13f  63–65 C,

½a20D   ¼ 21:16 (c = 1.0, CHCl3)}. Removal of the isopropylidene

group in 15 was achieved with Amberlyst-15 in THF/H2O (2:1) to

give (+) pentenomycin   2 in 75% yield, whose analytical data

were in good agreement with the reported values. {½a20D   ¼ þ30:8

(c = 0.14, EtOH), lit.:13f  ½a25D   ¼ þ30:1, (c = 0.1, EtOH)}. Again

attempts to continue the cascade reaction in the presence of Me2AlCl

in THF or DCM/THF along with Tebbe reagent on 13 have met with

failure.

The mechanism is depicted in Scheme 4 for the formation of

product 15. 1,3 Chelation of the alkoxyaluminum with ring oxygen

in 16 might have exerted effective activation for the opening of the

ring to give active species 17, which resulted in 18 through the

intramolecular aldol reaction via 5-(enol-endo)-exo-trig-cycliza-

tion. Further, 1,2 elimination has taken place in the same pot to

give required enone 15.

After successfully achieving (+) pentenomycin 2, we turned our

attention to synthesize the natural () pentenomycin 1 (Scheme

5). For this, the required lactone 1913f,22 was prepared from D-man-

nose in four steps. Ring opening of 19 with NaOH followed by

chopping the diol gave compound 20 in 80% yield. Lactone 9 was

obtained by treatment of 20 with acid in 2-propanol in 84% yield.

Tebbe olefination of 9 gave the enol ether 21 in 78% yield.

Compound   21 when subjected to Me2AlCl gave the required

compound 22, whose analytical data were in good agreement with

the reported values.12e,13e,f  {mp 63–65 C, lit.:11b,13a 63–66 C

½a20D   ¼ þ20:0 (c = 1.0, CHCl3)}. Removal of the isopropylidene

group in 22 was achieved with Amberlyst-15 in THF/H2O (2:1)

to give () pentenomycin 1 in 75% yield, whose analytical data

were in good agreement with the reported values. {½a20D   ¼ 31:0

(c = 0.35, EtOH), lit.:12,13 ½a21D   ¼ 32:0 (c = 0.30, EtOH)}.

To further understand the mechanism, we then applied this

reaction on unsubstituted enol ether 23 (Scheme 6) where there

is no possibility of above said 1,3 chelation. For this, compound 3

obtained fromD

-ribose was converted into23

.

10

When23

was sub- jected to various Lewis-acids including Me2AlCl as listed in Table 1,

the required product transformation was not observed, every time

decomposition occurred. This further supports the specific reactiv-

ity of Me2AlCl with 13 and 21 by 1,3 chelation which helped the

required transformation to occur.

In conclusion, we developed a Tebbe-mediated cascade method

for the synthesis of (+) and () pentenomycins.23 During this ap-

proach, we observed that the Tebbe reaction on tertiary substi-

tuted lactones 7 and 9 gave only enol ethers 13 and 21 instead of

the cyclopentitols which we observed earlier.10 For the transforma-

tion of 13 and 21 into cyclopentenones 15 and 22 different Lewis-

acids have been studied. It was found that Me2AlCl is a suitable re-

agent for this transformation which is taking place via 5-(enol-

endo)-exo-trig cyclization a disfavored transformation as per Bald-

win rules. The failure of Me2AlCl condition for the conversion of

simple enol ether 23 into 24 can be attributed to the lack of inter-

nal 1,3 chelation. Further applicability of this methodology is un-

der progress.

O

O   O

O

O

O   O

O

O

O Al

O   O

ORO

O

O O

O

OH13

15

1,2 eliminationintramolecular 

aldol reaction

 Al   Al

or HR =16 17

18

Scheme 4. Plausible mechanism for the formation of 15.

O

O O

OHO

HO

OH

O

O O

HO O

OH

O

O O

O   O

OH

O

O O

O

OHO   O

OH

19   20   9

21   22

a b  c

d O

HO

OH

O

OH

1

e

Scheme 5. Synthesis of () pentenomycin 1. Reagents and conditions: (a) (i) NaOH, H2O, 40 C, 20 min. (ii) NaIO4, 0 C, BaCl2, 30 min, 80%; (b) 2-propanol, PPTS (cat.), reflux,80 C, 1.5 h, 84%; (c) Tebbe reagent (1.8equiv), THF, 0C, 1 h, 78%; (d) Me2AlCl (1.2 equiv), 78 C, 20 min, 70%; (e) Amberlyst-15 in THF/H2O (2:1), 70C, 5 h, 75%.

O

O O

O   LA

Table 1

23

O

O O

O O

3

TebbeO   O

O

24

(1 equiv.)

Scheme 6. Study on unsubstituted enol ether.

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 Acknowledgments

B.S.K. and G.P.M. thank the CSIR (New Delhi) for fellowship. We

would like to thank the Director, CSIR-IICT for constant support.

Supplementary data

Supplementary data (general procedures and spectral data)associated with this article can be found, in the online version, at

http://dx.doi.org/10.1016/j.tetlet.2013.03.092 .

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