Catalytic asymmetric synthesis of enantiopure isoprenoid building blocks: application in the synthesis of apple leafminer pheromones

Abstract

The first catalytic asymmetric procedure capable of preparing all 4 diastereoisomers (ee > 99%, de > 98%) of a versatile saturated isoprenoid building block was developed and the value of this new method was demonstrated in its application to the concise total synthesis of two pheromones.

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The saturated isoprenoid unit is a central theme in many natural products including pheromones,¹ vitamins,² marine natural products,³ and archaebacterial lipids.⁴ Isoprenoid based chiral building blocks (Fig. 1) therefore constitute a major synthetic challenge to the field of total synthesis. Current methods to synthesize such building blocks include chiral pool strategies,^1b,5 enzymatic desymmetrization protocols^3b,6 and chiral auxiliary based approaches.^4b,7 However, all of these methods are inherently multistep and either incapable of delivering all diastereoisomers or use a stoichiometric amount of chiral material. As for asymmetric catalytic methods, only two examples have been reported in the literature. In 1987 Noyori employed a Ru–binap complex in the asymmetric hydrogenation of allylic alcohols to synthesize a C₁₅ chain containing a saturated syn-isoprenoid unit as present in the vitamins E and K.⁸ More recently, Negishi developed an elegant Zr-catalyzed enantioselective carboalumination to prepare such compounds.⁹ It should be noted though, that in both cases only the syn-isoprenoid unit has been synthesized and that one end of the molecule is restricted to a saturated alkyl chain.

Fig. 1 General structure of the saturated isoprenoid unit and structures of all diastereoisomers of the isoprenoid building block prepared by asymmetric catalysis.

Scheme 1 Synthesis of enantiopure building blocks.¹⁶ (a) Cu(OTf)₂ (5 mol%), L₁ (10 mol%), Me₂Zn (5.0 eq.), toluene, −25 °C, 12 h; (b) Cu(OTf)₂ (2.5 mol%), L₁ (5 mol%), Me₂Zn (1.5 eq.), CH₂Cl₂, −25 °C, 12 h, then Et₃N (3.0 eq.), TMEDA (5.0 eq.), TMSOTf (5.0 eq.), Et₂Zn (0.42 eq.), rt, 2 h; (c) Cu(OTf)₂ (2.5 mol%), ent-L₁ (5 mol%), Me₂Zn (1.5 eq.), CH₂Cl₂, −25 °C, 12 h, then Et₃N (3.0 eq.), HMPA (5.0 eq.), TMSCl (5.0 eq.), Et₂Zn (0.42 eq.), rt, 2 h; (d) O₃, MeOH, CH₂Cl₂, −78 °C, 15 min, then NaBH₄ (10 eq.), rt, 12 h; (e) MeOH, TMSCl (3.0 eq.), reflux, 12 h.

Scheme 2 Synthesis of apple leafminer pheromones. (a) p-TsCl, pyridine, 0 °C, 12 h; (b) DIBAH (5.0 eq.), Et₂O, −78 °C, 30 min; (c) CuBr·SMe₂ (1.0 eq.), n-PrMgBr (16 eq.), THF, −78 °C to 0 °C, 12 h; (d) CuBr·SMe₂ (21 mol%), 6-heptenylMgBr (4.0 eq.), THF, −78 °C to 0 °C, 12 h; (e) CuBr·SMe₂ (31 mol%), n-hexylMgBr (5.7 eq.), THF, −78 °C to 0 °C, 12 h.

In order to avoid these constraints in synthetic flexibility and stereocontrol, we have focused on a more general applicable method towards enantiopure saturated isoprenoid units. Herein we report a catalytic method which allows, for the first time, the synthesis of all 4 diastereoisomers (ee > 99%, de > 98%) of a versatile isoprenoid building block, capable of functionalization at both terminae (Fig. 1). Furthermore, we demonstrate the synthetic usefulness of the acquired building blocks by an application in the total synthesis of two pheromones.

Our method is based on the Cu-phosphoramidite catalyzed asymmetric conjugate addition of dialkylzinc reagents to cyclic substrates, developed in our group.¹⁰ We anticipated that this protocol, used iteratively in the conjugate addition of Me₂Zn to cycloocta-2,7-dienone (2) followed by oxidative ring opening (Fig. 2), would enable the rapid assembly of enantiopure syn- and anti-isoprenoid building blocks. However, as depicted in Fig. 2, quenching of the zinc enolate after the second conjugate addition with a proton source would result in a meso compound in case of the cis-adduct. To avoid a racemic product after ring opening, a procedure was developed, involving in situ trapping of the zinc enolate as a silyl enol ether and subsequent ring opening via ozonolysis (Scheme 1).¹¹

Fig. 2 General strategy for synthesizing enantiopure saturated isoprenoid building blocks; problem of formation of a meso compound.

Cycloocta-2,7-dienone (2) was prepared from cyclooctanone in one step via oxidation with IBX as described by Nicolaou et al.¹² Conjugate addition of Me₂Zn to 2 yielded 3 (ee > 99%) in 85% yield using 5 mol% catalyst, 5.0 eq. Me₂Zn and slow addition of the substrate to the reaction mixture over 5 h. When standard conditions were employed (2.5 mol% catalyst, 1.5 eq. Me₂Zn),^10c a significant amount of side product (4) was formed due to Michael addition of the zinc-enolate to the substrate (Scheme 1). In the second conjugate addition this side reaction was sufficiently suppressed by slow addition of the substrate allowing for the use of 2.5 mol% of catalyst. In the case of the trans-adduct, quenching the reaction with TMSOTf in the presence of Et₃N and TMEDA resulted in quantitative formation of the corresponding silyl enol ether 5a (ee > 99%, de > 98%). The cis-adduct 5b was formed (95% conversion as determined by ¹H–NMR) with excellent selectivity (ee > 99%, de > 98%) when HMPA and TMSCl were used instead of TMEDA and TMSOTf, as the latter reagents induced partial racemization.¹³ The silyl enol ethers (5a/5b) were ring-opened by ozonolysis and the resulting aldehyde was reduced upon work-up with NaBH₄. The crude carboxylic acids (6a/6b) were then heated under reflux in MeOH in the presence of TMSCl to give the methyl esters 1a and 1b in an overall yield of 45% from 3.¹⁴ As an alternative, the conversion of 3 into carboxylic acid 6a was performed as a one pot procedure, yielding 1a after esterification in 40% yield.¹⁵ The enantiomers of all compounds in Scheme 1 were prepared by using the opposite enantiomer of the ligand, i.e. ent-L₁ in place of L₁ and vice versa.¹⁶

In summary, all 4 diastereoisomers of 1 were synthesized in excellent ee (>99%) and de (>98%) from 2 in 4 steps with an overall yield of 38%. It should be emphasized, that the resulting chiral building blocks, can be used in subsequent coupling reactions to prepare oligoprenoids of any desired length and stereochemistry. This novel approach should, therefore, show broad application in the total synthesis of a range of natural products and analogues thereof.

To demonstrate the synthetic versatility of this catalytic approach, it was employed in the total synthesis (Scheme 2) of two—female-produced—pheromones 11 and 12 of the apple leafminer (Lyonetia prunifoliella), a pest endemic to the eastern regions of North America.^17,18 The total synthesis required, that both ends of the anti-building block (1a) are elongated with alkyl chains. As a first step, the primary alcohol was converted into the tosylate 7 in 95% yield. Crude 7 was then treated with DIBAH to give the primary alcohol 8 in 94% yield. Subsequent chain elongation by reaction with a large excess of n-propylmagnesium bromide (16 eq.) in the presence of a stoichiometric amount of CuBr·SMe₂ gave 9 in excellent yield (99%).¹⁹ After conversion of the hydroxyl moiety of 9 into a tosyl group (10, 94%), the product was applied in coupling reactions with 6-heptenylmagnesium bromide and hexylmagnesium bromide in the presence of CuBr·SMe₂ to give 11 and 12, respectively, with full conversion.²⁰ Further applications of this strategy are currently under investigation in our laboratory.

We would like to thank T.D. Tiemersma-Wegman (GC) and A. Kiewiet (MS) for technical support. This work was supported by the Dutch Organization for Scientific Research (NWO).

Notes and references

1. (a) K. Mori, in The Total Synthesis of Natural Products, ed. J. ApSimon, Wiley-Interscience, New York, 1992, 9; (b) Y. Nakamura and K. Mori, Eur. J. Org. Chem., 1999, 2175; (c) J. R. Aldrich, J. E. Oliver, W. R. Lusby, J. P. Kochansky and M. J. Borges, J. Chem. Ecol., 1994, 20, 1103.
2. (a) C. Mercier and P. Chabardes, Pure Appl. Chem., 1994, 66, 1509; (b) P. Dowd, R. Hershline, S. W. Ham and S. Naganathan, Nat. Prod. Rep., 1994, 11, 251.
3. (a) L. Minale, in Marine Natural Products, ed. P. J. Scheuer, Academic Press, 1978, vol. 1, ch. 4; (b) S. Sankaranarayanan, A. Sharma and S. Chattopadhyay, Tetrahedron: Asymmetry, 2002, 13, 1373.
4. (a) D. Zhang and C. D. Poulter, J. Am. Chem. Soc., 1993, 115, 1270; (b) W. F. Berkowitz and Y. Wu, J. Org. Chem., 1997, 62, 1536.
5. (a) T. Eguchi, K. Arakawa, T. Terachi and K. Kakinuma, J. Org. Chem., 1997, 62, 1924; (b) S. Hanessian, P. J. Murray and S. P. Sahoo, Tetrahedron Lett., 1985, 26, 5623.
6. R. Chênevert and M. Desjardins, J. Org. Chem., 1996, 61, 1219.
7. (a) C. H. Heathcock, B. L. Finkelstein, E. T. Jarvi, P. A. Radel and C. R. Hadley, J. Org. Chem., 1988, 53, 1922; (b) J. Fujiwara, Y. Fukutani, M. Hasegawa, K. Maruoka and H. Yamamoto, J. Am. Chem. Soc., 1984, 106, 5004; (c) A. Gambacorta, D. Tofani, P. Lupattelli and A. Tafi, Tetrahedron Lett., 2002, 43, 2195.
8. H. Takaya, T. Ohta, N. Sayo, H. Kumobayashi, S. Akutagawa, S. Inoue, I. Kasahara and R. Noyori, J. Am. Chem. Soc., 1987, 109, 1596.
9. S. Huo, J. Shi and E. Negishi, Angew. Chem. Int. Ed., 2002, 41, 2141.
10. (a) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos and A. H. M. De Vries, Angew. Chem. Int. Ed., 1997, 36, 2620; (b) B. L. Feringa, Acc. Chem. Res., 2000, 33, 346; (c) R. B. C. Jagt, R. Imbos, R. Naasz, A. J. Minnaard and B. L. Feringa, Isr. J. Chem., 2001, 41, 221.
11. O. Knopff and A. Alexakis, Org. Lett., 2002, 4, 3835.
12. K. C. Nicolaou, T. Montagnon, P. S. Baran and Y.-L. Zhong, J. Am. Chem. Soc., 2002, 124, 2245.
13. Partial racemization of the cis-adduct 5b upon use of TMSOTf is probably due to the fact that TMSOTf is reactive enough to convert small quantities of (meso) ketone into racemic 5b while TMSCl is not.
14. The main loss of product occurred in the purification of 5a/5b due to volatility of the silyl enol ethers. Therefore, CH₂Cl₂ was the solvent of choice in the second 1,4-addition, even though toluene gave similar conversions and equally high ee's and de's.
15. In this case the prime loss of product was due to oxidation of the aldehyde in the ozonolysis step.
16. (7S)- 3, (3S,7S)-1a and (3S,7R)-1b were isolated in comparable yield, ee and de as compared to their enantiomers.
17. For earlier synthesis of these pheromones see: Y. Nakamura and K. Mori, Eur. J. Org. Chem., 2000, 2745.
18. R. Gries, G. Gries, G. G. S. King and C. T. Maier, J. Chem. Ecol., 1997, 23, 1119.
19. The use of catalytic amounts of CuBr·SMe₂ or Li₂CuCl₄ and a smaller excess of Grignard reagent (5 eq.) was less successful, with incomplete reaction after 12 h and partial exchange of the tosyl group by bromide.
20. 12 was not separated from dodecane, which resulted from homocoupling of the Grignard. The estimated yield (GC) of 12 was 70%.

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Footnote

† Electronic supplementary information (ESI) available: detailed experimental procedures and spectroscopic (¹H and ¹³C NMR) and analytical data of all compounds in Schemes 1 and 2. Chiral GC-methods for determination of ee and de of compounds 3 and 5. See http://www.rsc.org/suppdata/cc/b4/b419268k/

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