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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Angew Chem Int Ed Engl. Author manuscript; available in PMC 2012 September 7.
Published in final edited form as:
PMCID: PMC3436603
NIHMSID: NIHMS379117

Synthesis of Enantioenriched α-(Hydroxyalkyl)-tri-n-butylstannanes**

Abstract

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A catalytically asymmetric synthesis of α-(hydroxyalkyl)-tri-n-butylstannanes 1 in good-excellent yields and enantioselectivities (up to 98% e.e.) via addition of ethyl(tri-n-butylstannyl)zinc to aldehydes was achieved. In practice, 1 was isolated after protection as its more stable ester or thiocarbamate (PG). The reagent was prepared from equimolar amounts of tri-n-butylstannyl hydride and Et2Zn in DME so as to avoid contamination by lithium and magnesium ions which suppress enantioselectivity.

Keywords: aldehydes, asymmetric synthesis, organometallic compounds, tin, zinc

α-(Hydroxyalkyl)triorganostannanes are versatile synthetic intermediates that have found wide applicability in natural products total synthesis.[1] Most notably, they offer a higher level of structural and stereochemical complexity compared with their tetraorganotin congeners, yet still participate in a variety of stereospecific transformations including transition metal catalyzed cross-couplings,[2] generation of configurationally stable anions,[3] Wittig rearrangements,[4] SE’-additions to carbonyls,[5] nucleophilic displacements,[6] and other reactions.[7] Numerous synthetic strategies to enantioenriched α-(hydroxyalkyl)triorganostannanes have been devised, inter alia, (i) asymmetric reduction of acyl stannanes,[8] (ii) classical resolution,[9] (iii) enzymatic resolution,[10] (iv) cleavage of C2-symmetric stannyl acetals,[11] (v) electrophilic stannylation,[12] and (vi) nucleophilic stannylation,[13] however, the goal of a widely applicable, economic and operationally simple synthesis from readily available starting materials remains elusive. Herein, we report the catalytically asymmetric synthesis of α-(hydroxyalkyl)-tri-n-butylstannanes 1 i n g o o d-excellent yields and enantioselectivities via addition of ethyl(tri-n-butylstannyl)zinc to aldehydes (eq 1). In practice, 1 was isolated after protection as its more stable ester or thiocarbamate (PG).

equation image
(eq 1)

Bolstered by the precedent of catalytic, asymmetric organozinc additions to carbonyls[14] and the equally well documented preparation of racemic α-(hydroxyalkyl)triorganostannanes from aldehydes and ketones using triorganostannyl nucleophiles,[15] we were attracted to the possibility of comparable asymmetric additions of tri-n-butylstannylzinc reagents to aldehydes. Yet, this proved not to be straightforward. Despite extensive attempts using tri-n-butylstannyllithium or Grignard[16] in combination with various ratios with zinc halides and chiral ligands, 1 (PG = Ac) was generated with little, if any, useful enantioselectivity, albeit in good yield. Reasoning the Li or Mg-ions might have detrimental effects, alternative approaches to stannylzinc generation were systematically investigated. Finally, we were gratified to discover that addition of ethyl(tri-n-butylstannyl)zinc,[17] generated in situ via transmetalation of tri-n-butyltin hydride with diethylzinc,[18] to benzaldehyde (2) in the presence of (S)-α,α-diphenyl-2-pyrrolidinemethanol (3, 10 mol %) at −40 °C in DME afforded adduct 4 in poor yield, but undeniably good stereoselectivity (i.e., 95% ee), following in situ acetylation (Table 1, entry 1).[19] In the absence of catalyst 3, the uncomplexed organozinc reagent was lifeless under the same conditions (entry 2); aldehyde addition did not proceed at an appreciable rate until 4 °C (entry 3). Higher temperatures (entry 4) improved the yield modestly, but eventually started a downward trend in the % ee (entry 5). The most significant improvement was achieved with a 4-fold excess of ethyl(tri-n-butylstannyl)zinc (entry 6) which when combined with a doubling of the catalyst loading to 20 mol%, boosted the yield still further (entry 7), although further increases in the mol% catalyst had no effect (entry 8). THF (entry 9) and Et2O (entry 10) were less effective as solvents compared with DME; toluene, CH2Cl2, acetonitrile and hexane were not suitable.

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Table 1
Reaction parameters.[a]

Evaluation of a series of commercial, chiral diphosphine, diamine, and amino-alcohol catalysts under the reaction conditions described in Table 1, entry 7, revealed the latter were the most efficacious (see Supporting Information). In concert with the proposed structure for other chiral zinc intermediates,[20] the amine can be either secondary (e.g., 3) or tertiary (e.g., 5 and 7, Fig. 1), but the alcohol should be unsubstituted for maximum asymmetric induction (e.g., 3 vs. 6).

Figure 1
Preparation of 4 using select chiral catalysts.

To help define the scope of the reaction, a panel of representative aldehydes was subjected to asymmetric stannylation (Table 2). In the case of propionaldehyde (8), the absolute configuration of the adduct 9 (entry 1) was established by comparisons (optical rotation, chiral HPLC) with a standard of known stereochemistry.[11b,21] Dihydrocinnamaldehyde (10) was likewise well behaved and gave rise to acetate 11 (entry 2) and thiocarbamate 12 (entry 3) with equal ease, although catalyst 7 furnished a somewhat better enantioselectivity than 3. As expected, the antipode of 12, i.e., 13 (entry 4), was formed in virtually the same yield and optical purity when 3 was replaced by (R)-α,α-diphenyl-2-pyrrolidinemethanol [(R)-3]. The trend of superior enantioselectivity with 7 and slightly better yields with 3 continued with cyclohexanecarboxaldehyde (14, entry 5), but was not as evident for the related aromatic, benzaldehyde (2, entry 6). The ortho-substituent of 2-tolualdehyde (16, entry 7) did not significantly influence the reaction, but the presence of an electron-donating para-methoxy (entry 8) and even a para-bromo (entry 9) were well tolerated. On the other hand, moderately strong electron-withdrawing substituents, viz., methoxycarbonyl (entry 10), cyano (entry 11), and trifluoromethyl (entry 12), seemed to lower the enantioselectivity. It was gratifying to find that, despite the reputation of stannyl anion as a good Michael nucleophile,[22] its addition to E,E-farnesal (28) under our standard conditions produced allylic adduct 29 in useful yield and high % ee (entry 13).

Table 2
Asymmetric synthesis of protected α-(hydroxylalkyl)-tri-n-butylstannanes.[a]

In summary, this report describes a convenient, widely applicable, and highly enantioselective preparation of protected α-hydroxyalkylstannanes and, thus, should expedite applications of this intriguing, but comparatively inaccessible class of tin reagents. We hope, in the future, to extend these studies to other electrophiles, e.g., imines (eq 2).

equation image
(eq 2)

Experimental Section

General procedure: n-Bu3SnH (1.06 mL, 4 mmol) was added dropwise to a stirring, −78 °C solution of Et2Zn (4 mL, 1M in hexane) in anhydrous DME (10 mL) under an argon atmosphere. After 5 min, the reaction mixture was warmed to 4 °C and kept at this temperature for 1 day. Upon dilution with more DME (27 mL), the reaction mixture was re-cooled −78 °C and the catalyst (0.2 mmol) in DME (2 mL) and aldehyde (1 mmol) in DME (1 mL) were added sequentially. After 5 min, the temperature was raised to the level indicated in the table and maintained using a cryogenic cooler. After complete reaction, typically 3-6 h, AcCl (0.2 mL) was added and the reaction mixture was warmed to rt over 0.5 h. After another 2 h, the reaction mixture was subjected to extractive isolation using CH2Cl2 and the crude product was purified by SiO2 column chromatography.

For the thiocarbamate, the reaction mixture was quenched with saturated aq. NH4Cl, extracted with CH2Cl2 (3 × 50 mL), and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude α-hydroxyalkylstannane was re-dissolved in CH2Cl2 (10 mL) to which was added Im2C(S) (2 mmol) and DMAP (10 mol%) at rt. After ~ 2 h, the reaction mixture was filtered through a short pad of silica gel. The silica gel pad was rinsed with hexane (40 mL) first to remove the non-polar tin byproduct, then with hexane/EtOAc (1:1, 100 mL). The combined filtrates were concentrated in vacuo. The residue was immediately dissolved in neat, anhydrous pyrrolidine (2 mL) at rt. Evaporation of the pyrrolidine after 1 h and purification of the residue by SiO2 column chromatography affords α-thiocarbamoyl protected stannane.

For the 4-nitrobenzoate (29), the reaction mixture was quenched with saturated aq. NH4Cl, extracted with CH2Cl2 (3 × 15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude α-hydroxyalkylstannane was protected directly by stirred with 4-nitrobenzoyl chloride (0.5 mmol), Py (0.2 mL) in CH2Cl2 (10 mL) at rt. After ~ 4 h, the reaction was quenched with water, extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by SiO2 column chromatography.

Supplementary Material

Supporting Information

Acknowledgments

Dedicated to Professor E. J. Corey on the occasion of his 80th birthday

Footnotes

[**]We thank the NIH (GM31278, DK38226) and the Robert A. Welch Foundation for financial support.

Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author.

References

[1] Representative examples: Falck JR, Barma DK, Mohapatra S, Bandyopadhyay A, Reddy KM, Qi J, Campbell WB Bioorg. Med. Chem. Lett. 2004;14:4987–4990. [PubMed]
; Ye J, Bhatt RK, Falck JR Tetrahedron Lett. 1993;34:8007–8010.
; Marshall JA, Yashunsky DV J. Org. Chem. 1991;56:5493–5495.
; Chong JM, Mar EK Tetrahedron. 1989;45:7709–7716.
; Fouquet E, Herve A In: Handbook of Functionalized Organometallics. Knochel P, editor. Vol 1. Wiley-VCH Verlag GmbH & Co.; Weiheim, Germany: 2005. pp. 203–249.
[2]a) Ye J, Bhatt RK, Falck JR. J. Am. Chem. Soc. 1994;116:1–5.b) Falck JR, Bhatt RK, Ye J. J. Am. Chem. Soc. 1995;117:5973–5982.c) Linderman RJ, Siedlecki JM. J. Org. Chem. 1996;61:6492–6493. [PubMed]
[3]a) Christoph G, Stratmann C, Coldham I, Hoppe D. Org. Lett. 2006;8:4469–4471. [PubMed]b) Dieter RK, Watson RT, Goswami R. Org. Lett. 2004;6:253–256. [PubMed]c) Linderman RJ, Siedlecki J, O’Neill SA, Sun H. J. Am. Chem. Soc. 1997;119:6919–6920.d) Bhatt RK, Ye J, Falck JR. Tetrahedron Lett. 1996;37:3811–3814.e) Linderman RJ, Griedel BD. J. Org. Chem. 1991;56:5491–5493.f) Chan PCM, Chong JM. Tetrahedron Lett. 1990;31:1985–1988.g) Lesimple P, Beau JM, Sinay P. Carbohydr. Res. 1987;171:289–300.h) McGarvey GJ, Kimura M. J. Org. Chem. 1985;50:4655–4657.i) Still WC, Sreekumar C. J. Am. Chem. Soc. 1980;102:1201–1202.
[4]a) Maleczka RE, Jr., Geng F. J. Am. Chem. Soc. 1998;120:8551–8552.b) Tomooka K, Komine N, Nakai T. Synlett. 1997:1045–1046.c) Tomooka K, Igarashi T, Watanabe M, Nakai T. Tetrahedron Lett. 1992;33:5795–5798.
[5] Marshall JA, Welmaker GS, Gung BW. J. Am. Chem. Soc. 1991;113:647–656.
[6]a) Mohapatra S, Bandyopadhyay A, Barma DK, Capdevila JH, Falck JR. Org. Lett. 2003;5:4759–4762. [PubMed]b) Ye J, Shin D-S, Bhatt RK, Swain PA, Falck JR. Synlett. 1993:205–206.c) Chong JM, Park SB. J. Org. Chem. 1992;57:2220–2222.
[7]a) Kagoshima H, Shimada K. Chem. Lett. 2003;32:514–515.b) Chong JM, Mar EK. J. Org. Chem. 1992;57:46–49.
[8] Chan PCM, Chong JM. J. Org. Chem. 1988;53:5584–5586.
[9]a) Kells KW, Nielsen NH, Armstrong-Chong RJ, Chong JM. Tetrahedron. 2002;58:10287–10291.b) Linderman RJ, Cusack KP, Jaber MR. Tetrahedron Lett. 1996;37:6649–6652.c) Jephcote VJ, Pratt AJ, Thomas EJ. J. Chem. Soc., Perkin Trans. 1. 1989:1529–1535.
[10]a) Chong JM, Mar EK. Tetrahedron Lett. 1991;32:5683–5686.b) Itoh T, Ohta T. Tetrahedron Lett. 1990;31:6407–6408.
[11]a) Cintrat J-C, Blart E, Parrain J-L, Quintard J-P. Tetrahedron. 1997;53:7615–7628.b) Tomooka K, Igarashi T, Nakai T. Tetrahedron Lett. 1994;35:1913–1916.
[12] Gralla G, Wibbeling B, Hoppe D. Tetrahedron Lett. 2003;44:8979–8982.
[13] Bhatt RK, Ye J, Falck JR. Tetrahedron Lett. 1994;35:4081–4084.
[14] Reviews: Dimitrov V, Kostova K Lett. Org. Chem. 2006;3:176–182.
; Pu L, Yu H-B Chem. Rev. 2001;101:757–824. [PubMed]
[15]a) Linderman RJ. In: Encyclopedia of Reagents for Organic Synthesis. Paquette LA, editor. Vol. 7. Wiley; Chichester: 1995. pp. 5026–5029.b) Sato T. Synthesis. 1990:259–270.
[16] Podlech J. Sci. Syn. 2003;5:285–297.
[17] Whilst ethyl(tri-n-butylstannyl)zinc (i) is generated using equimolar amounts of reagents, other species such as ii may be present.
equation image
[18] At odds with our experience, at least one laboratory has reported transmetalation of trialkylstannyl hydrides with dialkylzinc leads to decomposed products: Des Tombe FJA, Van Der Kerk GJM J. Organomet. Chem. 1972:247–252.
[19] It’s instructive that similar additions [2, ethyl(tri-n-butylstannyl)zinc (4 equiv), 3 (20 mol%) in DME] when conducted in the presence of LiBr (2 equiv) at −78 °C and −20 °C furnished 4 in 53% and 76% yields, respectively, but 0% ee. Presumably, Lewis acids such as Li+ (and likely Mg2+) are capable of catalyzing the addition of uncomplexed stannylzinc to aldehydes. This would explain why reagents generated from stannyllithium and - magnesium halide were not useful for asymmetric additions.
[20] Erdik E. Organozinc Reagents in Organic Synthesis. CRC; Boca Raton, FL: 1996. Chap. 4; pp. 108–206.
[21] The absolute configurations of all other adducts were assigned in analogy. Catalysts 3 and 7 furnished the same major stereoisomer in entries 3, 5, 6, and 8.
[22] For example see, Kirschning A, Harders J Synlett. 1996:772–774.