Garner's aldehyde as a versatile intermediate in the synthesis of enantiopure natural products

Abstract

Since its introduction to the synthetic community in 1984, Garner's aldehyde has gained substantial attention as a chiral intermediate for the synthesis of numerous amino alcohol derivatives. This review presents some of the most successful carbon chain elongation reactions, namely carbonyl alkylations and olefinations. The literature is reviewed with particular attention on understanding how to avoid the deleterious epimerization of the existing stereocenter in Garner's aldehyde.

Keywords: Garner’s aldehyde; L-serine; asymmetric synthesis; natural product synthesis.

Figure 1

Structures of limonene, carvone and thalidomide.

Figure 2

Structure of Garner’s aldehyde.

Scheme 1

(a) i) Boc₂O, 1.0 N NaOH (pH >10), dioxane, +5 °C → rt; ii) MeI, K₂CO₃, DMF, 0 °C → rt (86% over two steps); (b) Me₂C(OMe)₂, cat. p-TsOH, benzene, reflux (70–89%); (c) 1.5 M DIBAL-H, toluene, −78 °C (76%).

Scheme 2

(a) AcCl, MeOH, 0 °C → reflux (99%); (b) i) (Boc)₂O, Et₃N, THF, 0 °C → rt → 50 °C (89%); ii) Me₂C(OMe)₂, BF₃·Et₂O, acetone, rt (91%).

Scheme 3

(a) LiAlH₄, THF, rt (93–96%); (b) (COCl)₂, DMSO, iPr₂NEt, CH₂Cl₂, −78 °C → −55 °C (99%).

Scheme 4

The Koskinen procedure for the preparation of Garner’s aldehyde. (a) i) AcCl, MeOH, 0 °C → 50 °C (99%); ii) (Boc)₂O, Et₃N, CH₂Cl₂, 0 °C → rt (95–99%); (b) Me₂C(OMe)₂, BF₃·Et₂O, CH₂Cl₂, rt (86%, after high vacuum distillation); (c) DIBAL-H, toluene, −84 °C (EtOAc/N₂ bath) (82–84%, after high vacuum distillation).

Scheme 5

Burke’s synthesis of Garner’s aldehyde. BDP - bis(diazaphospholane).

Figure 3

Structures of some iminosugars (7, 9), peptide antibiotics (8) and sphingosine (10) and pachastrissamine (11).

Scheme 6

Use of Garner’s aldehyde 1 in multistep synthesis.

Scheme 7

Explanation of the anti- and syn-selectivity in the nucleophilic addition reaction.

Scheme 8

Herold’s method: (a) Lithium 1-pentadecyne, HMPT, THF, −78 °C (71%); (b) Lithium 1-pentadecyne, ZnBr₂, Et₂O, −78 °C → rt (87%). Garner’s method: (c) Lithium 1-pentadecyne, THF, −23 °C (83%); (d) 1-Pentadecyne, DIBAL-H, hexanes/toluene, −78 °C (>80%).

Scheme 9

(a) Ethyl lithiumpropiolate, HMPT, THF, −78 °C; (b) (S)- or (R)-MTPA, DCC, DMAP, THF, rt (18, 81%) or (19, 87%).

Scheme 10

Coleman’s selectivity studies and their transition state model for the co-ordinated delivery of the vinyl nucleophile.

Scheme 11

(a) PhMgBr, THF, −78 °C → 0 °C [62] or (a) PhMgBr, Et₂O, 0 °C [63].

Scheme 12

(a) cat. RhCl₃·3H₂O, cat. 26, NaOMe, Ph-B(OH)₂, aq DME, 80 °C (24, 71%); (b) cat. RhCl₃·3H₂O, cat. 26, NaOMe, C₆H₁₃CH=CH₂-B(OH)₂, aq DME, 55 °C (25, 78%).

Scheme 13

Lithiated dithiane (3 equiv), CuI (0.3 equiv), BF₃·Et₂O (6 equiv), THF, −50 °C, 12 h (70%).

Scheme 14

Addition reaction reported by Lam et al. (a) 1-Hexyne, n-BuLi, THF, −15 °C or −40 °C.

Scheme 15

(a) n-BuLi, HMPT, toluene, −78 °C → rt (85%); (b) n-BuLi, ZnCl₂, toluene/Et₂O, −78 °C → rt (65%).

Scheme 16

(a) n-BuLi, 34, THF, −40 °C [69]; (b) n-BuLi, 35, THF, −78 °C → rt (80%) [70]; (c) n-BuLi, 35, HMPT, THF, −78 °C (87%) [71].

Scheme 17

(a) cat. Rh(acac)(CO)₂, 42, THF, 40 °C (74%).

Scheme 18

(a) 1-PropynylMgBr, CuI, THF, Me₂S, −78 °C (95%); (b) Ethynyltrimethylsilane, EtMgBr, CuI, THF, Me₂S, −78 °C (82%) [72]; (c) EthynylMgCl, ZnBr₂, toluene, −78 °C [73]; (d) n-BuLi, methyl propiolate, Et₂O, −78 °C → 0 °C, then (S)-1 at −20 °C (62%) [74].

Scheme 19

(a) cat. 50, toluene, 0 °C (52%); (b) cat. 51, toluene, 0 °C (51%); (c) cat. 52, toluene, 0 °C (50%).

Scheme 20

(a) (iPr)₃SiH, cat. Ni(COD)₂, dimesityleneimidazolium·HCl, t-BuOK, THF, rt.

Scheme 21

(a) Cp₂Zr(H)Cl, cat. AgAsF₆, CH₂Cl₂, rt; (b) Cp₂Zr(H)Cl, 1-pentadecyne, cat. ZnBr₂ in THF for anti-selective or ZnEt₂ in CH₂Cl₂ for syn-selective reaction. (c) Cp₂Zr(H)Cl, Et₂Zn, in CH₂Cl₂, for syn-selective reaction or in THF for anti-selective reaction.

Scheme 22

(a) i) 31, n-BuLi, THF, −78 °C; ii) (S)-1, THF, −78 °C; (b) Red-Al, THF, 0 °C.

Scheme 23

(a) 61, n-BuLi, DMPU, toluene, −78 °C, then (S)-1, toluene, −95 °C (57%); (b) 61, n-BuLi, ZnCl₂, toluene, −78 °C, then (S)-1, toluene, −95 °C (72%).

Scheme 24

Olefin A as an intermediate in natural product synthesis.

Scheme 25

(a) Ph₃(Me)PBr, KH, benzene (66%, rac-64) or (b) AlMe₃, Zn, CH₂I₂, THF (76%) [101]; (c) Ph₃(Me)PBr, n-BuLi, THF, −75 °C, then (S)-1 (27%, 69% ee) [102]; (d) 65, n-BuLi, THF, −75 °C, then (S)-1 (78%, 1:13 E/Z, >95% ee); (e) 67, KHMDS, THF, −78 °C, then (S)-1, quenching with MeOH (70%, >10:1 E/Z) [104].

Scheme 26

(a) Benzene, rt (82%) [108]; (b) K₂CO₃, MeOH (85%) [89]; (c) iPrOH, [Ir(COD)Cl]₂, PPh₃, THF, rt (81%) [114].

Scheme 27

Mechanism of the Still–Gennari modification of the HWE reaction leading to both olefin isomers.