Terpene Derived Auxiliaries: Miscellaneous Terpene Derived Auxiliaries

Terpene Derived Auxiliaries: Miscellaneous Terpene Derived Auxiliaries – Part 1

Authors: HE Ensley, MJ Reale


3.5.1 Miscellaneous Terpene Derived Chiral Auxiliaries Carene Derivatives

The enantiomers of (þ)-2-carene, 1, and (þ)-3-carene, 2, are not available; however in many reactions, reagents prepared from the two dextrorotatory isomers have opposite (but not equal) enantioselectivities (Figure 1).

Figure 1. (þ)-2-carene and (þ)-3-carene
Figure 1. (þ)-2-carene and (þ)-3-carene. Stoichiometric carene chiral auxiliaries

Brown has reported that both (þ)-2-carene and (þ)-3-carene can be purified to 499% enantiomeric excess (ee). Pure (þ)-2-carene is prepared by hydroboration of less pure (þ)-2-carene to give di-2-isocaranylborane which can be recrystallized from tetrahydrofuran (THF). The di-2-isocaranylborane prepared from (þ)-2-carene (2-dIcr2BH) is converted to a trialkylborane on reaction with a disposable 1-alkene (1-pentene or 1-hexene) and then treated with 2.5 equivalents of benzaldehyde at 60 1C to liberate pure (þ)-2-carene. Purified (þ)-3-carene can be prepared by recrystallization from pentane at  100 1C or by treatment of less pure 3-carene with 10 mol% 9-borabicyclononane (9-BBN) which consumes the more reactive unsaturated impurities usually found in 3-carene.1 Asymmetric hydroboration

Di-2-isocaranylborane (2-dIcr2BH, 3) can be prepared easily by the reaction of borane–dimethylsulfide complex with 2-carene. Similarly, di-4-isocaranylborane (4-dIcr2BH, 4) can be prepared by the reaction of borane–dimethylsulfide complex with 3-carene.1 Brown studied the hydroboration of alkenes with 3 and 4 and found that the two dialkylboranes have opposite enantioselectivites with di-(2-isocaranyl)borane having much higher enantioselectivity (Scheme 1). Both isomers showed highest enantioselectivity in the hydroboration of cis-disubstituted alkenes. The hydroboration of other alkenes showed little to moderate enantioselectivity. The (þ)-2-carene or (þ)-3-carene could be recovered from the hydroboration product by treatment with acetaldehyde or benzaldehyde.1

Scheme 1. Hydroboration of alkenes with 3 and 4. Asymmetric allylation of aldehydes

Methanolysis of the dialkylboranes 3 and 4, followed by treatment with allyl Grignard gives the trialkylboranes 2-dIcr2Ball, 6 and 4-dIcr2Ball, 8, respectively (Scheme 2).2 These reagents are usually very enantioselective in reactions with aldehydes to afford chiral butenols (Table 1). As was the case in hydroborations with 3 and 4, 6 and 8 show opposite enantioselectivity; however, in this case, the difference in enantioselectivity is usually small (see Chapter 6.8).

Scheme 2. Preparation of the trialkylboranes 2-dIcr2Ball 6 and 4-dIcr2Ball 8
Scheme 2. Preparation of the trialkylboranes 2-dIcr2Ball 6 and 4-dIcr2Ball 8.
Table 1 Comparison of asymmetric allylborations with B-allylbis(isocaranyl)boranes 6 and 8 at -78℃
AldehydeProduct alcoholReagent (% ee)
2-dIcr2Ball, 64-dIcr2Ball, 8
Acetaldehyde4-Penten-2-olS (98)R (94)
Propionaldehyde5-Hexen-3-olS (94)R (91)
n-Butyraldehyde1-Hepten-4-olS (94)R (89)
2-Methylpropionaldehyde2-Methyl-5-hexen-3-olR (94)S (95)
2,2-Dimethylpropionaldehyde2,2-Dimethyl-5-hexen-3-olR (99)S (88)
Acrolein1,5-Hexadien-3-olR (95)S (93)
Benzaldehyde1-Phenyl-3-buten-1-olR (95)S (87)
Source: Reproduced with permission from Table 1 in Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racheria, U. S. J. Am. Chem. Soc. 1990, 112(6), 2389–2392. © 1990 American Chemical Society.

Sammakia used the allylboration with compound 8 as a key step in the synthesis of the oxopolyene macrolide RK-397, an antifungal, antibacterial, and antitumor agent which was isolated from a soil bacteria (Streptomyces sp. 87–397). The achiral dialdehyde 9 prepared by diisobutylaluminum hydride (DIBAL-H) reduction of dimethylglutarate, was treated with B-allylbis(4-isocaranyl)borane, 8, to give diol, 10, as a 10:1 mixture of diastereomers (98% ee for the major isomer) in 53% overall yield from dimethylglutarate (Scheme 3).3

Scheme 3. Allylboration of achiral aldehyde 9 by treatment with B-allylbis(4-isocaranyl)borane 8 in the synthesis of the oxopolyene macrolide RK-397.

Brown extended the utility of the asymmetric allylation by preparation of the E- and Z-crotylbis(isocaranyl)boranes. Cis-2-butene was metalated by treatment with n-butyllithium (BuLi) and potassium t-butoxide in THF at -45℃ and then treated with B-methoxybis(2-isocaranyl)borane, 5, at -78℃ (Scheme 4). The resulting ate complex was then treated with BF3·OEt2 to give B-(Z)-crotylbis-(2-isocaranyl)borane, 11. The same procedure using trans-2-butene affords the E-isomer. Both the E- and Z-isomers of 11 are easy to prepare and give high enantioselectivity and diastereoselectivity in reactions with aldehydes (Table 2).4

Scheme 4. Preparation of B-(Z)-crotylbis-(2-isocaranyl)borane 11.

Brown later observed that the presence of magnesium salts, from the preparation of the allylating reagents 6 and 8, were detrimental to the rate of allyl transfer and to the enantioselectivity of the reaction. When a magnesium-free solution of B-allylbis(2-isocaranyl)borane was added to an aldehyde, the reaction was ssentially instantaneous at  100 1C. Also the enantioselectivities were 99 þ % with the B-allylbis(2-isocaranyl)borane, 6, and 96–99% with B-allylbis(4-isocaranyl)borane, 8. The two isomers still displayed opposite enantioselectivities.5

Table 2. Products from the crotylation of acetaldehyde and propionaldehyde with B-[Z]-crotylbis(2-isocaranyl)borane (11), B-[E]-crotylbis(2-isocaranyl)borane (12), B-[Z]-crotylbis(4-isocaranyl)borane (13), and B-[E]-crotylbis(4-isocaranyl)borane (14).

One problem which plagued the early use of B-allylbis(2-isocaranyl)borane and B-allylbis(4-isocaranyl)borane was the fact that the chiral reagent was destroyed during the oxidative workup of the hydroboration reaction. The production of two equivalents of 2-isocaranol or 4-isocaranol could make the isolation of the desired chiral alcohol product difficult. Brown et al. developed several procedures to overcome this problem.6 One procedure involves the treatment of the initially formed Icr2BOhomoallylic borinate ester with isobutyraldehyde and 1 mol% BF3  OEt2 at 65℃ to give 2-carene or 3-carene in 80–90% yield, along with the chiral homoallylic alcohol. The homoallylic alcohols can be isolated from this mixture by distillation. Alternatively, the initially formed Icr2BO homoallylic borinate ester can be treated with 8-hydroxyquinoline which liberates the homoallylic alcohol and forms the insoluble 8-hydroxyquinoline bis(isocaranyl)borane (8-HQ-BdIcr2) adduct. The 8-HQ-BdIpc2 adduct can be converted into the corresponding B-methoxybis(isocaranyl)borane esters (5 or 7, Scheme 2) by treatment with acidic methanol at 0℃ for 30 min in quantitative yield. The 8·HQ·HCl salt can be separated by filtration to give 5 and 7 for recycle.6 Enantioselective imine-anion alkylation

Shioiri developed a procedure for the preparation of chiral benzylamines by alkylation of the dianion formed by treatment of the Schiff base 15 with three equivalents of BuLi. (-)-3-Hydroxy-2-caranone, prepared from (+)-2-carene, was converted to the Schiff base by treatment with arylmethylamines. Lithiation followed by benzylation (at -78℃) and subsequent hydrolysis gave the chiral amines in moderate yields and 60–87% ee (Scheme 5).7 The procedure gave better results (90–98% ee) when (+)-2-hydroxy-3-pinanone (prepared from (-)-α-pinene) was used rather than (-)-3-hydroxy-2-caranone (see Chapters 3.3 and 6.1).

Scheme 5. Preparation of chiral benzylamines from the Schiff base 15
Scheme 5. Preparation of chiral benzylamines from the Schiff base 15. Chiral boron enolates

Fringuelli studied the reaction of boron enolates 16 of acetic acid, mono-, and disubstituted acetic acid with benzaldehyde (Scheme 6). The dilithiated acids (R1=H, Me, Et, Ph, OPh, or SMe and R2=H, Me, Et) were treated with (-)-di-2-isocaranylchloroborane or (-)-di-4-isocaranylchloroborane to give the corresponding boron enolates, 16a and 16b (16a, L=2-isocaranyl and 16b, L=4-isocaranyl), respectively (Scheme 7).8 Interestingly, the di-2-isocaranylboron enolates of acetic acid (16a, R1 = R2 = H) add to the re-face of benzaldehyde (72% ee) and the corresponding di-4-isocaranylboron enolate (16b, R1 = R2 = H) add to the si-face (42% ee) but when disubstituted acetates are used (R1 = R2 = Me or Et) both 16a and 16b add to the si-face with high enantioselectivity (94–99% ee). When benzaldehyde reacts with monosubstituted acetic acid boron enolates, the situation is more complicated but, in general, the di-2-isocaranylboron enolates give predominantly the syn-adduct with 80–95% ee and the di-4-isocaranyl analogs give predominantly the anti-adduct with lower selectivity (20–80% ee) and the chirality of the adducts are reversed.8

Scheme 6. Preparation and reactions of boron enolates 16 of acetic acid, mono-, and disubstituted acetic acid with benzaldehyde.
Scheme 7, Facial selectivities of the reaction of boron enolates 16a and 16b with benzaldehyde. Catalytic carene chiral auxiliaries Chiral aminoalcohols

Morpholine reacts with the epoxide of (+)-3-carene to give the aminoalcohol 17 (Scheme 8). DuPont workers found 17 to be a useful ligand for directing the addition of lithium cyclopropylacetylide to the ketimine 18 to give the dihydroquinazolinone 19, a second-generation nonnucleoside, reverse transcriptase inhibitor (equation 1)9 (see Chapters 3.16 and 3.20).

Scheme 8 Synthesis of aminoalcohol 17.

Although, in theory, aminoalcohol 17 could be used catalytically in the reaction, the optimum conditions required three equivalents of 17 (as well as three equivalent cyclopropylacetylene and six equivalent lithium bis(trimethylsilyl)amide (LiHMDS)) for each equivalent of 18. Under these conditions, the crude dihydroquinazolinone 19 was obtained with 94% ee. A single recrystallization gave 19 in 85% yield and 99.6% ee.9

Malhotra used the aminoalcohol 17 for the chiral addition of diethylzinc to a variety of aldehydes (Table 3) (see Chapter 3.24).

Table 3 Enantioselective addition of diethylzinc to aldehydes catalyzed by β-aminoalcohol 17
EntryAldehydeYield (%)ee (%)Configuration
Source: Reproduced from Table 2 in Joshi, S. N.; Malhotra, S. V. Tetrahedron: Asymmetry 2003, 14(13), 1763–1766.

The aminoalcohol 17 was used at 15 mol% (in toluene at 20℃) and gave good yields with moderate to excellent selectivity (72–98% ee) for the R-alcohol. The enantioselectivity was explained by the transition state shown in Figure 2 which involves re-face attack on the aldehyde.10

Figure 2. Transition state of the chiral addition of diethylzinc to various aldehydes using aminoalcohol 17. Chiral bipyridyl ligands

Malkov et al. prepared a number of chiral bipyridine ligands from (+)-2-carene and (+)-3-carene. Ligand 20 was prepared from (+)-3-carene by Negishi coupling of the pyridyl triflate (Scheme 9).11 Since the enantiomer of (+)-3-carene is not available, ent-20 cannot be prepared the same way; however, Malkov prepared the quasienantiomer of 20, compound 21, from (+)-2-carene. A third ligand, 22, was prepared from (+)-3-carene which not only had a similar chirality to 21 but also had a wider chiral cavity.

The copper(I) complexes of the three ligands were prepared and the catalytic activity was evaluated in allylic oxidation of 5-, 6-, and 7-membered cycloalkenes. The bipyridine copper(I) complexes of 20 and 21 have a narrow chiral cavity whereas the chiral cavity of 22 is wider. This difference in cavity shape was used to explain the lower enantioselectivity of the 22 copper complex. The copper(I) complex of 21 gave the higher enantioselectivity and, as expected, 20 and 21 gave opposite enantiomers (Table 4).11

The copper(I) complex of 21 also catalyzed the asymmetric cyclopropanation of styrene (see Chapter 6.11). In the presence of 1 mol% of catalyst, treatment with tert-butyl diazoacetate gave a 96% yield of a 86:14 mixture of trans- and cis-isomers (equation 2). The trans-isomer was produced in 59% ee (1S,2S).11

Scheme 9. Preparation of chiral bipyridine ligands 20, 21, and 22 from (+)-2-carene and (+)-3-carene.
Table 4. Asymmetric allylic oxidation of cyclopentene, cyclohexene, and cycloheptene catalyzed by Cu(I) complexes of chiral ligands 20, 21,
and 22 (1 mol%) using tert-butylperbenzoate in acetone
EntryLigandAlkeneTemperature (℃)Time (h)Yield (%)ee (%), (Configuration)
120Cyclohexene2025855, (S)
221Cyclopentene2019643, (R)
321Cyclohexene2059866, (R)
421Cyclohexene0487670, (R)
521Cyclohexene-20963377, (R)
621Cyclopentene20126072, (R)
721Cyclopentene0485775, (R)
821Cyclopentene-20963582, (R)
922Cyclohexene20245235, (R)
Source: Reproduced from Table 1 in Malkov, A. V.; Pernazza, D.; Bell, M.; et al. J. Org. Chem. 2003, 68(12), 4727–4742, with permission from American Chemical Society.

Chelucci prepared a bis-N,N`-dioxide similar to 20–22 but with an isopropylidene spacer group separating the pyridine rings (equation 3). The bis-N,N`-dioxide was used as a catalyst (10 mol% in acetonitrile) for the allylation of benzaldehyde using allyltrichlorosilane; however, the yield of (S)-1-phenyl-3-buten-1-ol was low (22%) and the enantioselectivity (35% ee) was lessthan the corresponding bis-N,N`-dioxide prepared from pinocarvone (58% yield and 83% ee).12


1. Brown, H. C.; Vara Prasad, J. V.; Zaidlewicz, M. J. Org. Chem. 1988, 53(13), 2911–2916.

2. Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racheria, U. S. J. Am. Chem. Soc. 1990, 112(6), 2389–2392.

3. Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T. Angew. Chem. Int. Ed. 2007, 46(7), 1066–1070.

4. Brown, H. C.; Randad, R. S. Tetrahedron 1990, 46(13-14), 4457–4462.

5. Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56(1), 401–404.

6. Brown, H. C.; Racherla, U. S.; Liao, Y.; Khanna, V. V. J. Org. Chem. 1992, 57(24), 6608–6614.

7. Irako, N.; Hamada, Y.; Shioiri, T. Tetrahedron 1995, 51(46), 12731–12744.

8. Fringuelli, F.; Piermatti, O.; Pizzo, F. J. Org. Chem. 1995, 60(21), 7006–7009.

9. Kauffman, G. S.; Harris, G. D.; Dorow, R. L.; et al. Org. Lett. 2000, 2(20), 3119–3121.

10. Joshi, S. N.; Malhotra, S. V. Tetrahedron: Asymmetry 2003, 14(13), 1763–1766.

11. Malkov, A. V.; Pernazza, D.; Bell, M.; et al. J. Org. Chem. 2003, 68(12), 4727–4742.

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