Organoboranes for Syntheses - American Chemical Society

Chapter 10

Enantioselective Cyclopropanation Using Dioxaborolane Ligands Downloaded by UNIV OF MISSOURI COLUMBIA on September 11, 2014 | http://pubs.acs.org Publication Date: February 26, 2001 | doi: 10.1021/bk-2001-0783.ch010

A n d r é Β. Charette and Carmela Molinaro Département de Chimie, Université de Montréal, P.O. 6128, Station Downtown, Montréal, Québec H 3 C 3J7, Canada

Enantiopure cyclopropanes are important subunits found in several natural products. This chapter will highlight our efforts to design a stoichiometric chiral additive for the enantioselective cyclopropanation of allylic alcohols (Eq 1). Some preliminary mechanistic features of the cyclopropanation reaction in the presence of dioxaborolane 1 and related analogs will also be presented.

(1)

yield > 80% ee : 90-94%

136

© 2001 American Chemical Society In Organoboranes for Syntheses; Ramachandran, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

137 I. Synthesis The chiral dioxaborolane 1 can be prepared using either one of two procedures. Originally, this dioxaborolane was generated under dehydrating conditions by using two readily available precursors : N N, N', Ν'-tetramethylL-tartaramide 2 and butylboronic acid 3 (Eq 2). These two precursors are commercially available, or easily prepared from tartaric acid (in the case of the tartaramide (44)) and from butyl magnesium bromide and trimethyl borate (in the case of the butylboronic acid (45)). Downloaded by UNIV OF MISSOURI COLUMBIA on September 11, 2014 | http://pubs.acs.org Publication Date: February 26, 2001 | doi: 10.1021/bk-2001-0783.ch010

,

Me NO(^

^CONMe

2

HO

2

OH

2

Me NOC Dean-Stark, reflux Œ

H[ÔH

85% yield 94% ee

96% yield 85% ee

93% yield 91% ee

Bu3Sn^>ÔH

85% yield 88% ee

88% yield 90% ee

r ^ ^ o n 83% yield 90% ee

Figure 1 : Representative examples of enantioenriched cyclopropylmethanols obtained from allylic alcohols using the dioxaborolane ligand 1 and bis(iodomethyl)zinc. The dioxaborolane-mediated cyclopropanation can also be used in the reagent-controlled cyclopropanation of chiral non-racemic f'-allylic alcohols (46) to effectively give uwii-cyclopropylmethanols (47) (Figure 2). Conversely, the cyclopropanation of Z-allylic alcohols produces mainly the syn- isomer. The ^//-selective cyclopropanation of chiral £-allylic alcohols is quite unique since the same reaction carried in the absence of the chiral additive produces the syn isomer (48). However, the level of uw/z-selectivity is highly dependant upon the nature and size of the substituents on the alkene and on the allylic position.

OH

98% yield ÔH

\ / TIPSO

77% yield > 95% ee 19:1 de

OH %

* 88% yield 94% ee > 5 0 : 1 de

Figure 3 : Representative examples of enantioenriched cyclopropylmethanols obtained from polyenes, homoallylic alcohols using the dioxaborolane ligand 1 and bis(iodomethyl)zinc and allylic alcohols from functionalized zinc reagents.

III. Mechanistic Considerations The dioxaborolane ligand 1 was designed such that it possesses both, a Lewis basic site (the amide groups) that will chelate to the cyclopropanating reagent (bis(iodomethyl)zinc) and a Lewis acidic site (the boron center) that will allow binding to the allylic alcohol (or its corresponding zinc alkoxide). According to our studies, the first step of the reaction is the deprotonation of the alcohol by the cyclopropanating reagent to form a zinc alkoxide and methyl iodide. It is postulated that the resulting basic zinc alkoxide covalently binds to the boron center to form a tetracoordinate borate intermediate. Boron N M R of the reaction mixture indicates that a new species appearing at about 10 ppm is formed in small amounts. This chemical shift is consistent with the formation of a tetracoordinate boron species corresponding to ( R O ^ B B u . It is believed that the zinc reagent then complexes one of the amide groups, and a subsequent diastereoselective intramolecular delivery of the methylene group on one of the

In Organoboranes for Syntheses; Ramachandran, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

140 two faces of the double bond leads to the product. This species is converted to the corresponding cyclopropylmethanol upon work-up (Figure 4). Zn(CH I) 2

R 2

+

V

Me NOQ

Downloaded by UNIV OF MISSOURI COLUMBIA on September 11, 2014 | http://pubs.acs.org Publication Date: February 26, 2001 | doi: 10.1021/bk-2001-0783.ch010

2

R £ONMe

2

OH R

R

OZnCH I 2

J

R

3

CH I

+

3

Me NOC^

^CONMe

2

Bu

2

y

0

Bu

Me NO' 2

£ONMe

2

.CONMe

Me NO Highly Diastereoselective 2

2

Bu ICH Zh 2

Figure 4 : Proposed mechanism of the dioxaborolane ligand 1. The following transition state model shown in Figure 5 is consistent with the observed absolute configuration of the cyclopropane. The butyl substituent adopts a pseudoequatorial position and the allylic alkoxide a pseudoaxial position. It is believed that the reacting conformer is that in which the A strain is minimized. 1 , 3

Figure 5 : Chem 3D representation of the proposed transition state using dioxaborolane 1 and the zinc alkoxide of cinnamyl alcohol


141


IV. Other Dioxaborolanes The dioxaborolane structure was altered to understand the importance of the acidic and basic sites, and to better understand the essential structural features of the chiral additive for high enantioselectivities. The acidic site was first removed by replacing the boron center by a tetrahedral carbon. Racemic cyclopropylmethanol was obtained in quantitative yield when cinnamyl alcohol was cyclopropanated in the presence of dimethyl tartramide 5 under the usual conditions (Eq 4). This information suggests that the boron is necessary to bring the substrate and the ligand together and that the chiral additive does not act strictly as an activator of the bis(iodomethyl)zinc reagent. Me NOC

£ONMe

2

5

y P h ^ ^ O H

— Zn(CH l) /CH2ei2 2

2

2

Ρ Ι ΐ φ ^ Ο Η

(4)

> 95% yield 0% ee

The second site to be altered was the alkyl substituent on the boron center. Initially, it was proposed that the nature of this group should not have a major impact on the level of enantioselection of the cyclopropanation reaction. It is believed that this group simply adopts the pseudoequatorial position of the envelope conformation of the five-membered ring. Several different dioxaborolane ligands were prepared by the same method as that reported earlier. Four novel dioxaborolane additives were prepared with R = Me, Ph, 2naphthyl and 2,4,6-trimethylphenyl. The enantioselectivities observed for the cyclopropanation reaction are shown in Table I. In all the cases, the enantioselectivities were in the same range as that obtained with R = Bu, except for the 2,4,6-trimethylphenyl substituent. This information suggests that a sterically encumbered substituent on boron may partially prevent the postulated association between the zinc alkoxide and the boron center. In that case, the non-boron-assisted pathway can eventually become competitive. We finally turned our attention to the nature of the basic groups of the dioxaborolane additive. Initially, we tested additives in which the basic amides were completely removed and replaced with non-basic groups. The ligand derived from trans-



142

Table I : Variation of the alkyl substituent on dioxaborolane 1. Me NOQ

CONMe

2

2

γ R OH

ΌΗ Zn(CH I) / CH2C1 2

Entry

2

2

R

Ee (%)

Me Bu Ph 2-Naphthyl

93 93 92 92

90



143 dihydroxystilbene was synthesized and tested (entry 1, Table II). As expected, racemic cyclopropane was obtained when this additive was added to the cyclopropanation of cinnamyl alcohol. By replacing the amide groups with the less basic isopropyl or ethyl esters (entries 2 and 3, Table II), the enantioselectivity was almost completely lost and the other enantiomer of the cyclopropylmethanol was favored. This observation is quite intriguing and it may result from a competitive complexation o f the reagent by the dioxaborolane oxygen groups. Conversely, replacement o f the dimethylamides with the pyrrolidine amide (or with diethylamide) does not significantly alter the level of enantioselection (entry 6, Table II). However, the enantiomeric excesses are lower i f the methylamides that contain potentially acidic protons are used (entry 4, Table II). Interestingly, the removal of one of the dimethylamide groups leads to much lower selectivity (entry 5, Table II). This observation can be explained by the initial formation of a tetracoordinate boron center that may be non-selective and irreversible. One of the two diastereomeric complexes would lead to high enantioselectivities whereas its diastereomer would lead to racemic cyclopropane (Figure 6).

high ee's

low ee's

Ph Figure 6 : Diastereomeric complexes proposed when using dioxaborolane 6. In the last example (entry 7, Table II) a sterically constrained analogue of dioxaborolane of ligand 1 gave similar results as the ester derivatives. This may be explained by the fact that the amide groups in this systems are thought to be less basic than the dimethylamide analogue since the nitrogen lone pair cannot be perfectly delocalized in the carbonyl group.


144 Table II : Variation of the amides on dioxaborolane 1.

ν

Bu

PK

Zn(CH I) / CH C1 Downloaded by UNIV OF MISSOURI COLUMBIA on September 11, 2014 | http://pubs.acs.org Publication Date: February 26, 2001 | doi: 10.1021/bk-2001-0783.ch010

2

2

2

OH

2

Entry

R

R'

Ee (%)

1 2 3 4 5

Ph C0 Et CO^-Pr CONHMe CONMe

Ph C0 Et CO^-Pr CONHMe Η

0 41* 29* 63 70*

2

2

6

2

86

33^

other enantiomer

V. Synthetic Applications The enantioselective cyclopropanation reaction described herein has been used in several syntheses of cyclopropane-containing natural and non-natural products (52-67). Several examples are shown in Figure 7.

VI. Conclusions

A n effective, practical and readily available chiral modifier was developed for the effective enantioselective cyclopropanation of several allylic alcohols using bis(iodomethyl)zinc. Several chemical modifications have revealed a unique cooperativity between the boron acidic center and the basic amide groups. These observations and a better understanding o f the structure/selectivity relationship of the chiral additive should lead to an improved cyclopropanation system.



145

Halicholactone: Χ = CH2CH2 Neohalicholactone: Χ = cw-CH=CH

'"•OH Ο

OH

FR-900848

Η Ο U-106305 Figure 7 : Examples of cyclopropane-containing natural products where the methodology described herein is used.


146


References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.

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Organoboranes for Syntheses - American Chemical Society

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