182 Org. Synth. 2013, 90, 182-189 Published on the Web 3/4/13

© 2013 Organic Syntheses, Inc.

Discussion Addendum for:

Stereoselective Synthesis of anti -Methyl- -Methoxy

Carboxylic Compounds

1. TiCl4, i-Pr2NEt, CH2Cl2, –78 °C

2. BF3•OEt2, 1

A.

CH3NH(OCH3)•HClEt3N, DMAP

CH2Cl2, rt

B.

2 3

Amberlyst 15CH3OH

C.

HC(OMe)3, rt

NS

S O OMe

N

O OMe

MeO

Me

NS

S O

2

NS

S O OMe

OMe

OMe

O

H

Submitted by Pedro Romea* and Fèlix Urpí.*1

Original article: Gálvez E.; Romea P.; Urpí F. Org. Synth. 2009, 86, 81–91.

Prior and subsequent to our original report in Organic Syntheses, we

have described a number of highly diastereoselective Lewis acid-mediated

additions of titanium enolates from chiral N-acyl thiazolidinethiones to

acetals.2 These involve the addition of N-propanoyl and N-acetyl-4-

isopropyl-1,3-thiazolidine-2-thione to dialkyl acetals (eq 1 and 2 in Scheme

1)3-5

and dimethyl ketals from methyl ketones (eq 3 in Scheme 1).6

Furthermore, the scope of the acyl groups has been recently expanded to N-

glycolyl derivatives. Especially, O-pivaloyl protected N-glycolyl 4-

isopropyl-1,3-thiazolidine-2-thione undergoes highly diastereoselective

additions to a wide array of dimethyl and dibenzyl acetals (eq 4 in Scheme

1).7

DOI:10.15227/orgsyn.090.0182

Org. Synth. 2013, 90, 182-189 183

Scheme 1. Stereoselective additions of titanium enolates from

N-acyl-4-isopropyl-1,3-thiazolidine-2-thione to dialkyl acetals and ketals

(1)

(3)

R1: Me, Bn

(2)

(4)

R1: Me, Bn

L: H, Me, OPiv

NSL

S OTiCl4

NS

S O

R

OMe

NS

S O

ROPiv

OR1

NS

S O

R

OR1

NS

S O

R

OMe

BF3·OEt2 or SnCl4

R

OMeMeO

OR1

RR1O

SnCl4

BF3·OEt2 or SnCl4

OMe

RMeO

BF3·OEt2 or SnCl4

OR1

RR1O

These reactions likely proceed through a mechanism in which an

oxocarbenium intermediate approaches to the less hindered face of the

titanium enolate. Taking advantage of such a picture, this chemistry has been

successfully applied to glycals. Thereby, activation of glycals by Lewis

acids triggers the formation of cyclic and conjugated oxocarbenium

intermediates that may participate in highly diastereoselective - and -C-

glycosidation processes with the abovementioned titanium enolates.

Importantly, the appropriate choice of the chiral auxiliary and the C6-

protecting group determines the stereochemical outcome of these carbon-

carbon bond forming reactions and permits the modular preparation of three

of the four possible diastereomers of - or -1'-methyl-substituted C-

glycosides (Scheme 2).8-10

Scheme 2. Stereoselective C-glycosidation reactions

NS

S OTiCl4

NS

S OTiCl4

O

OAcOAc

OPGH

NS OOPG

S

H

OOAc

H

NS OOTBS

S

H

OOAc

H

NS OOAc

S

H

OOAc

H

SnCl4PG: Ac PG: TBS

dr 92:8dr > 98:2

79%94%

dr 99:1 97%

dr 82:18 94%

1'

6

1'

6

1'

6

61

184 Org. Synth. 2013, 90, 182-189

Synthetic applications

These methods have been already applied to the synthesis of natural

products. For instance, our group took advantage of the Lewis acid-mediated

addition of the titanium enolates from (S) N-acetyl and N-propanoyl 4-

isopropyl-1,3-thiazolidine-2-thiones (1 and 2 respectively in Scheme 3) to

dialkyl acetals for the construction of the C9–C21 fragment of

debromoaplysiatoxin.11

As shown in Scheme 3, chromatographic

purification of the product formed from the reaction between 1 and the

dimethyl acetal of an aromatic aldehyde afforded diastereomerically pure

adduct 3 in 82% yield. Removal of the chiral auxiliary gave alcohol 4, which

was further elaborated to chiral dibenzyl acetal 5. Then, the stage was set for

the introduction of two new stereocenters. Indeed, the asymmetric induction

imparted by the titanium enolate of 2 and the Felkin bias of the

oxocarbenium cation from 5 provided adduct 6 as a single diastereomer (dr

> 98:2) in 74% yield. Finally, treatment of 6 with MeNHOMe furnished

Weinreb amide 7 in 90% yield.12

Scheme 3. Stereoselective synthesis of C9–C21 fragment of

debromoaplysiatoxin

NS

S O1) TiCl4, i-Pr2NEt

2) BF3·OEt23-BnOPhCH(OMe)2

NS

S O

OBn

OMeNaBH4

HO

OBn

OMe

1 3 4dr 87:13 82%

87%

OBn

OMe

5

BnO

OBn

several steps

NS

S O

2) SnCl4NS

S O

MeNHOMe·HCl

2

6dr > 98:2 74%

OBn

OBn

OMe

N

O OBn

OBn

OMe

MeO

Me

Et3N, cat DMAP

7

90%

O

OO

O OMe

OH

O

OOH

Debromoaplysiatoxin

TiCl4 i-Pr2NEt

1)

9

21

9

21

Crimmins and Chakraborty have also used these transformations in

the total syntheses of pironetin and a protected form of the monomeric unit

Org. Synth. 2013, 90, 182-189 185

of rhizopodin respectively (Scheme 4).13,14

Thereby, Crimmins reported that

the addition of 2 to a chiral dimethyl acetal provided adduct 8 as a single

diastereomer in 64% yield, which was further converted into aldehyde 9 by

treatment with i-Bu2AlH (eq 1 in Scheme 4).13

In turn, Chakraborty

described a similar process involving an achiral dimethyl acetal in which

adduct 10 was obtained in an excellent diastereomeric ratio (dr 93:7) and

86% yield (eq 2 in Scheme 4).14

Interestingly, removal of the chiral auxiliary

by the lithium salt of the dimethyl methylphosphonate furnished

ketophosphonate 11 ready to participate in an HWE olefination.

Scheme 4. Total syntheses of pironetin and a monomeric unit of rhizopodin

NS

S O1) TiCl4, i-Pr2NEt

2)

NS

S O OMei-Bu2AlH

H

OMe

2 8 9

dr 98:2 64%

88%MeO

OMe

SnCl4

(1)

O

NS

S O1) TiCl4, i-Pr2NEt

2)

NS

S O OMe

OMe2 10

11

dr 93:7 86%

92%MeO

OTBDPSOMe

OTBDPS

SnCl4

(2)

OTBDPSO

MeOP LiO

MeO

PMeOMeO

O

O

O

Et

OH OMe

NOTBDPS

OMeOOMeOHTBSOO

OMeOMeTBSOMeO2C

2923

2923

147

147Pironetin

Protected monomeric unit of rhizopodin

Other reports have also established that these Lewis acid acid-

mediated couplings of N-acyl thiazolidinethiones and acetals are flexible

enough to be successfully adapted to the synthesis of a broad array of natural

products. For instance, Crimmins took advantage of the highly

diastereoselective reaction of the titanium enolate from N-(4-pentenoyl)

thiazolidinethione 12 and a dibenzyl acetal, the mild removal of the chiral

auxiliary from adduct 13, and the RCM of the resultant alcohol 14 to obtain

in a few steps the cyclic core 15 of aldigenin B (eq 1 in Scheme 5).15

In turn,

Hodgson reported that the addition of the titanium enolate of (R)-

186 Org. Synth. 2013, 90, 182-189

phenylglycine-derived N-acetyl thiazolidinethione 16 to the benzaldehyde

diallyl acetal provided diastereomerically pure adduct 17 in 74% yield after

chromatography. Further treatment of this adduct with magnesium

acetoacetate and imidazole led to -keto ester 18, a key intermediate in the

total synthesis of hyperolactone C (eq 2 in Scheme 5).16

Finally, the

synthesis of hennoxazole A by Smith includes a comprehensive study on the

Lewis acid-mediated additions of N-acetyl thiazolidinethiones to the

dimethyl acetal of bisoxazole 19.17

This revealed that the ability of an

oxazole nitrogen atom to coordinate with the titanium center altered the

stereochemical outcome of such additions and the undesired diastereomer

was obtained in 80:20 diastereomeric ratio and 67% yield. Looking for

alternative conditions, Smith found that the enolization of N-acetyl

thiazolidinethione 20 using Sammakia's conditions (PhBCl2/sparteine)

followed by the BF3 OEt2-mediated addition of the resultant boron enolate to

19 provided the desired adduct 21 in 86:14 diastereomeric ratio and 53%

yield (eq 3 in Scheme 5). Eventually, reduction of 21 with i-Bu2AlH gave

aldehyde 22, which was immediately used in the next step.

Scheme 5. Total syntheses of aldigenin B, hyperolactone C, and

hennoxazole

OH

NS

S O1) TiCl4, i-Pr2NEt

2)

NS

S O OBnLiBH4

12 13

dr 94:6 67%

90%

SnCl4

(1)

BnO

BnO

OH OBn

14

OH OBnG2

98%

15

O OBr

O

Ph

NS

S O1) TiCl4, i-Pr2NEt

2)Ph

NS

S O OMg(O2CCHCO2Et)

16 17

dr 86:14 74%

80%

BF3·OEt2

(2)

AllylO Ph

AllylO

18

O O

EtO

O

Imidazole

Ph O

O

OO

NS

S O1) PhBCl2, sparteine

2)

NS

S O OMe

i-Bu2AlH

20 21

dr 86:14 53%

BF3·OEt2

(3)

OTES MeO

OMe

O

N

N

O

TBSO

N

N

O

TBS

OTES

19 O OMe

O

N

N

O

TBS

H

22

O

OH

MeO H

OMe

O

N

N

O

Hennoxazole AAldingenin B Hyperolactone C

7 1

17

13

1 3

6

6

Org. Synth. 2013, 90, 182-189 187

Dialkyl acetals are not the only suitable substrates for these

transformations. Certainly, oxocarbenium cations from cyclic hemiacetals

and glycals (see Scheme 2) can also undergo highly diastereoselective

additions to titanium enolates from N-acyl thiazolidinethiones, as was used

by our group in the stereoselective synthesis of the western hemisphere of

salinomycin. Indeed, the SnCl4-mediated addition of the titanium enolate

from N-butanoyl thiazolidinethione 23 to hemiacetal 24 afforded -C-

glycoside 25 as a single diastereomer (dr > 97:3), which was treated with

methanol to obtain methyl ester 26 in 75% overall yield (eq 1 in Scheme

6).18

More recently, Leighton has reported that the coupling of structurally

complex O-acetyl hemiacetal 27 with the titanium enolate of ent-2 produced

-C-glycoside 28 as a single diastereomer in an outstanding 91% yield (eq 2

in Scheme 6).19

Methanolysis proceeded exceptionally smoothly to give 29

in quantitative yield, which was finally converted into zincophorin methyl

ester in a few steps.

Scheme 6. Syntheses of antibiotic polyethers

NS

S O1) TiCl4, i-Pr2NEt

2) SnCl4

23

dr > 97:3

(1)

NS

S O1) TiCl4, i-Pr2NEt

2) SnCl4

ent-2

Single diastereomer 91%

(2)

AcO OOBn

H

O O

O

OTBS

NS

S O

OOBn

H H

O O

O

OTBS

MeO

O

OOBn

H H

O O

O

OTBS

28MeOH

cat DMAP99%

29

OH

OBn

OMeOH

OBn

NS

S O

H

OH

OBnMeO

O

H

25

MeOH, cat DMAP

75% over two steps

26

OH

MeO

O

H

OH O OTBS

OBn

MeO

O

OH H

OH OH OH OH

24

27

Zincophorin methyl ester

Western hemisphere of salinomycin

188 Org. Synth. 2013, 90, 182-189

In summary, the Lewis acid-mediated addition of titanium enolates

from N-acyl thiazolidinethiones to dialkyl acetals, hemiacetals, or glycals

represents a powerful synthetic tool for the stereoselective construction of

carbon-carbon bonds leading to anti -alkyl- -alkoxy carboxylic

derivatives. Importantly, the chiral auxiliary can be easily removed using a

number of mild conditions, which confers to these methodologies a

remarkable appeal for the synthesis of natural products.

1. Departament de Química Orgànica, Universitat de Barcelona, Martí i

Franqués 1-11, 08028 Barcelona, Catalonia, Spain. E-mail:

pedro.romea@ub.edu; felix.urpi@ub.edu. Financial support from the

Spanish Ministerio de Ciencia e Innovación (MICINN), Fondos

FEDER (Grant No. CTQ2009-09692), and the Generalitat de Catalunya

(2009SGR825) are acknowledged.

2. For the influence of the chiral auxiliary on the stereochemical outcome

of these transformations, see: Baiget, J.; Cosp, A.; Gálvez, E.; Gómez-

Pinal, L.; Romea, P.; Urpí, F. Tetrahedron 2008, 64, 5637–5644.

3. Cosp, A.; Romea, P.; Talavera, P.; Urpí, F.; Vilarrasa, J.; Font-Bardia,

M.; Solans, X. Org. Lett. 2001, 3, 615–617.

4. Cosp, A.; Romea, P.; Urpí, F.; Vilarrasa, J. Tetrahedron Lett. 2001, 42,

4629–4631.

5. Cosp, A.; Larrosa, I.; Vilasís, I.; Romea, P.; Urpí, F.; Vilarrasa, J.

Synlett 2003, 1109–1112.

6. Checa, B.; Gálvez, E.; Parelló, R.; Sau, M.; Romea, P.; Urpí, F.; Font-

Bardia, M.; Solans, X. Org. Lett. 2009, 11, 2193–2196.

7. Baiget, J.; Caba, M.; Gálvez, E.; Romea, P.; Urpí, F.; Font-Bardia, M.

J. Org. Chem. 2012, 77, 8809–8814.

8. Larrosa, I.; Romea, P.; Urpí, F.; Balsells, D.; Vilarrasa, J.; Font-Bardia,

M.; Solans, X. Org. Lett. 2002, 4, 4651–4654.

9. Gálvez, E.; Larrosa, I.; Romea, P.; Urpí, F. Synlett 2009, 2982–2986.

10. Gálvez, E.; Sau, M.; Romea, P.; Urpí, F.; Font-Bardia, M. Tetrahedron

Lett. 2013, 54, 1467–1470.

11. Cosp, A.; Llàcer, E.; Romea, P.; Urpí, F. Tetrahedron Lett. 2006, 47,

5819–5823.

12. For an approach to the synthesis of the -amino acid embedded in the

structure of bistramides based on this chemistry, see: Gálvez, E.;

Parelló, R.; Romea, P.; Urpí, F. Synlett 2008, 2951–2954.

Org. Synth. 2013, 90, 182-189 189

13. Crimmins, M. T.; Dechert, A.-M. R. Org. Lett. 2009, 11, 1635–1638.

14. Pulukuri, K. K.; Chakraborty, T. K. Org. Lett. 2012, 14, 2858–2861.

15. Crimmins, M. T.; Hughes, C. O. Org. Lett. 2012, 14, 2168–2171.

16. Hodgson, D. M.; Man, S. Chem. Eur. J. 2011, 17, 9731–9737.

17. Smith, T. E.; Kuo, W.-H.; Balskus, E. P.; Bock, V. D.; Roizen, J. L.;

Theberge, A. B.; Carroll, K. A.; Kurihara, T.; Wessler, J. D. J. Org.

Chem. 2008, 73, 142–150.

18. Larrosa, I.; Romea, P.; Urpí, F. Org. Lett. 2006, 8, 527–530.

19. Harrison, T. J.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011, 133,

7308–7311.

Pedro Romea completed his BSc in Chemistry in 1984 at the

University of Barcelona. That year, he joined the group of

Professor Jaume Vilarrasa, at the University of Barcelona,

receiving his Master Degree in 1985, and he followed PhD

studies in the same group from 1987 to 1991. Then, he joined

the group of Professor Ian Paterson at the University of

Cambridge (UK), where he participated in the total synthesis of

oleandolide. Back to the University of Barcelona, he became

Associate Professor in 1993. His research interests have

focused on the development of new synthetic methodologies

and their application to the stereoselective synthesis of

naturally occurring molecular structures

Fèlix Urpí received his BSc in Chemistry in 1980 at the

University of Barcelona. In 1981, he joined the group of

Professor Jaume Vilarrasa, at the University of Barcelona,

receiving his Master Degree in 1981 and PhD in 1988, where

he was an Assistant Professor. He then worked as a NATO

postdoctoral research associate in titanium enolate chemistry

with Professor David A. Evans, at Harvard University (USA).

He moved back to the University of Barcelona and he became

Associate Professor in 1991. His research interests have

focused on the development of new synthetic methodologies

and their application to the stereoselective synthesis of

naturally occurring molecular structures.