Garner’s Aldehyde as a unique building block for synthesis of chiral drugs
More than 20 years ago, chemist Philip P. Garner reported the synthesis and configurational stability of a differentially protected serinal equivalent 1 (Figure 1) (Garner 1984, Garner & Park 1987), which today is commonly referred to as Garner’s Aldehyde. Since its disclosure, both enantiomers of 1 have been widely used as chiral building blocks in stereoselective synthesis of sophisticated molecules like amino acids, amino alcohols and amino sugars (Liang et al. 2001). Therefore, 1 embodies a prominent representative of the so-called chiral pool.
Projected commercial interest in Garner’s Aldehyde 1 stems from its pronounced utility in short-step synthesis of pharmaceuticals or drug candidates bearing one or more chiral centers (Figure 1). In line with this, a plethora of biologically active molecules differing in structure were synthesized from 1 in few steps. For example, 1 was the starting material in the synthesis of imino sugar C-glycosides (Takahata et al. 2004), carbacepham antibiotics (Avenoza et al. 2002), NMDA antagonists (Muller et al. 1993), natural antibiotic furanomycin (VanBrunt & Standaert 2000) and furanomycin derivatives via chiral allens (Erdsack & Krause 2013), and glycosphingolipid glucocerebroside (Murakami et al. 2005). In a similar way, 1 has been taken as the starting point in the synthesis of Furo[3,2-b]furan-2-ones (Erdsack et al. 2007).
Garner’s aldehyde 1 is unstable in both strong acidic and basic media. Prolonged exposure of 1 to acidic conditions causes ketal degradation and cleavage of the BOC-protecting group, whilst certain basic reaction conditions cause racemization of the chiral center. To that end, more resilient building blocks based on 1 are highly desirable for reactions carried out under harsh conditions. A protecting group swap from BOC into more stable substituents such as CBZ (Z) or Tosyl (Ts) offers the easiest way, yielding much more viable molecular structures of type 2 and type 3 (Figure 2). Synthetic intermediates derived from 2 or 3 may turn out to be much more robust than their BOC-protected counterparts. For instance, application of N-tosyl auxiliaries of type 3 can result in isolation of crystalline material rather than oily compounds (Erdsack et al. 2008). Recently, a more advanced building block derived from 1, alkyne 4, has become a matter of particular interest (Benfodda et al. 2015).
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© Ghostwriter Naturwissenschaften (2019)
Key Words: Asymmetric Synthesis, Chiral Pool, Garner’s Aldehyde, Natural Product Synthesis, Protective Groups