Synthesis of cyclopropane containing natural products

About: This article is published in Tetrahedron.The article was published on 2001-10-08 and is currently open access. It has received 512 citations till now. The article focuses on the topics: Cyclopropane.

Summary

Introduction

• Recent developments in cyclopropane ring formation which have had a major impact on the synthesis of natural products will first be covered, followed by the applications of these methods.
• This may be rationalized by interconversion of (R)- and (S)-68 via ring opening to the π-allyl-Pd intermediate 72a (Fig. 10).

3.3.1. Anthroplalone and noranthroplone

• In 1990, Kakisawa and coworkers reported the isolation of two cyclopropyl containing natural products from the Okinawan actinia Anthopleura pacifica.83 83b.
• The absolute configuration of 112 and 113 at the cyclopropane ring was proposed on the basis of the known absolute configuration of 114 and their proposed biosynthetic pathway.
• McMurry and Bosch reported the preparation of rac-112 as an intermediate in their synthesis of rac-114 (Scheme 21).
• Transformation of the methyl ketone to a methyl group was accomplished by standard methodology to yield 121.
• Julia-type olefination of ketone 122 with the phenylsulfone 123 gave olefin 124 as an inseparable mixture of isomers (E/Z=1:2.6).

3.3.2. Dictyopterenes

• A variety of brown seaweeds indigenous to Hawaii, Japan and Australia produce an odiferous mixture of volatile C11 hydrocarbons.
• Reduction and elimination gave (+)-133 as a mixture of E- and Zisomers; separable by chromatography over AgNO3 impregnated silica gel.
• Schaumann's group reported a synthesis of (+)-133 based on a homoallyl-cyclopropylcarbinyl cation rearrangement (Scheme 31).98 Reaction of (S)-glycidol tosylate with the anion of 3-trimethylsilylpropyne gave the homopropargylic alcohol 159.
• Removal of the TBS protecting group, oxidation and Wittig olefination completed the preparation of (+)-133.

3.3.3. Constanolactones, halicholactone, and solandelactones

• Certain marine invertebrates and algae produce cyclopropyl containing eicosanoids.
• Critcher, Connolly, and Wills were the first to report a total synthesis of halicholactone and neohalicholactone (Scheme 39).
• In a fashion similar to the synthesis of 199 from this same group (Scheme 38), deprotection and oxidation of (−)-4 yielded the aldehyde ent-195.
• Recently, Luithle and Pietruszka reported preparation of the bis-cyclopropane segment 250 via sequential cyclopropanations (Scheme 48).28., 131.

3.6.1. Metal catalyzed diazomethane cyclopropanation

• Ohfune's group has made extensive use of Pd-catalyzed diazomethane cyclopropanation for the preparation of CCG's.
• While the Pd catalyzed diazomethane cyclopropanation of acyclic allylic amines proceeds with low diastereoselectivity, similar cyclopropanation of cyclic olefins bearing a stereodirecting substituent proceeds with good diastereoselectivity.
• The authors propose that the abstraction of the C2′ proton is rate determining and that the resultant carbanion is immediately reprotonated by the in situ generated TMS2NH.

3.6.2. Metal catalyzed diazocarbonyl cyclopropanation

• Both Ohfune's144 and Pellicciari's145 groups reported that intermolecular addition of ethyl diazoacetate to either the protected allylic amine 316 or the antipodal N-Boc d-vinylglycine methyl ester 317 gave a mixture of all four possible diastereomeric cyclopropanes, predominating in the trans-isomers (Scheme 59).
• Notably, the lowest energy conformer positions the NHCbz group perpendicular to the olefin in order to maximize overlap of the C–N σ-bond with the π∗-antibonding orbital of the enoate and also positions the OBO group further away from the enoate in order to minimize steric interactions.

3.6.3. Sulfoxonium ylide cyclopropanation

• Demir and coworkers reported a synthesis of the parent trans-CCG which uses an enantioselective oxime reduction.
• Ma and coworkers explored the diastereoselective addition of sulfoxonium ylides to chiral electron deficient olefins (see Scheme 4).
• Cleavage of the acetonide, followed by Jones oxidation and finally ester saponification and removal of the Boc group completed this synthesis.

3.6.4. Cyclopropanation via MIRC reaction

• Chavan and coworkers reported a short synthesis of rac-303 (Scheme 71).
• The stereochemical assignments of the products were based on extensive NMR data, including nOe difference experiments.
• This is indicated in the insert for one enantiomer of the enoate.
• A recent route to 2-(2′,3′-dicarboxycyclopropyl)glycine 355 reported by Marinozzi and Pellicciari154 utilizes the chiral trans-chloroallyl phosphonamide reagent E-56 (Scheme 5) pioneered by Hanessian's group.
• A second ozonolysis, this time of the vinyl phosphonamide group, with oxidative workup and diazomethane esterification yielded the diester 369.

Figures

Figure 10.

Figure 15.

Figure 16.

Figure 4.

Figure 5. Ligands for asymmetric Simmons–Smith.

Figure 17.

Table 1. Enantioselective Simmons–Smith cyclopropanation

Table 2. Intermolecular enantioselective cyclopropanation of styrene with alkyl diazoacetate

Figure 6. 2.3. Olefin-diazoester cyclopropanation29 The preparation of cyclopropanecarboxylates via decomposition of diazoacetates in the presence of olefins has been known for nearly 100 years. Many transition metal complexes (Fig. 7) are known to catalyze this reaction, and the associated problems of diastereoselectivity (i.e. trans vs cis) and enantioselectivity may be addressed by varying the metal–ligand system, as well as the steric bulk of the ester group. A select compilation of results for the enantioselective cyclopropanation of styrene with alkyl diazoacetates are presented (Eq. (10), Table 2).30., 31., 32., 33., 34., 35., 36., 37., 38., 39., 40., 41. In general, copper based catalysts are superior to rhodium dimers, and in most cases, the trans isomer predominates. Increasing the steric bulk of the ester group may increase the trans-20/cis-21 ratio. Only a few chiral catalysts lead to a predominance of the cis-21 isomer (entries 11 and 12); in these cases, the ee for cis-21 was greater than that for trans-20.(10)

Figure 7.

Figure 19.

Figure 22.

Table 3. Diazomethane cyclopropanation of E-allylic amines

Figure 1.

Figure 13.

Figure 21.

Figure 14.

Figure 11. Conformational analysis of 84 and 86.

Figure 8.

Table 4. Diazomethane cyclopropanation of N,O-acetonides

Figure 20.

Frequently asked questions

Q1. how was the formation of the nine-membered lactone ring accomplished?

Formation of the nine-membered lactone ring was accomplished by esterification with 5-hexenoic acid followed by ring closing metathesis using Grubbs' catalyst. 

Q2. What is the t-butyl ester of lactone 206?

The t-butyl ester of lactone 206 was transformed into an aldehyde 207 by hydrolysis, reduction of the mixed anhydride and TPAP oxidation. 

Q3. What was the reaction of the amide with the sulfone 297?

Reduction of the amide gave the protected cyclopropylcarbinol, which underwent subsequent Mitsunobu substitution and oxidation to afford the sulfone 297. 

Q4. What was the reaction of the rac-292?

Reduction of the ester and protection of the resultant 1° alcohol provided rac-290, which was subjected to lithium–tin exchange and methylation to give rac-291a. 

Q5. What is the reaction that produced the glycine functionality?

Oxidation of the resultant 1° alcohol to the aldehyde set the stage for introduction of the glycine functionality via an asymmetric Strecker reaction. 

Q6. What is the way to prepare a polycyclopropane fragment?

et al. utilized an iterative homoallyl to cyclopropylcarbinyl carbocation rearrangement (cf. Scheme 7) for the preparation of a biscyclopropane fragment. 

Q7. What is the structure of the benzyl ether 277?

The structure of 277, which contains a trans-divinylcyclopropane unit, was established by spectroscopic analysis, as well as X-ray structure of the 1,5,6-triformate (278) derived via reduction of the C1 carboxylic acid group followed by reaction with DMF/Br2. 

Q8. What was the reaction of the cyclopropyl sulfone 297?

The C9–C13 cyclopropyl sulfone 297 was coupled with the C1–C8 aldehyde 298 via a Julia olefination to give mixture of isomeric olefins 299 (E/Z=2.6:1) (Scheme 54).