Multigram Synthesis of Advanced 6,6-Difluorospiro[3.3]heptane-derived Building Blocks

Abstract

A convenient methodology for constructing 6,6-difluorospiro[3.3]heptane scaffold – a conformationally restricted isostere of gem-difluorocycloalkanes – is developed. Alarge array of novel 2-mono- and 2,2-bifunctionalized difluorospiro[3.3]heptane building blocks was obtained through the convergent synthesis strategy using a common synthetic precursor – 1,1-bis(bromomethyl)-3,3-difluorocyclobutane. The target compounds and intermediates were prepared by short reaction sequences (6–10 steps) on multigram scale (up to 0.47 kg).

Graphical Abstract

Spiro compounds

An approach to 6,6-difluorospiro[3.3]heptane scaffold – a conformationally restricted isostere of gem-difluorocycloalkanes – is developed. A large array of novel 2-mono- and 2,2-difunctionalized 6,6-difluorospiro[3.3]heptane building blocks was obtained in multigram scale through the convergent synthesis strategy using a common synthetic intermediate – 1,1-bis(bromomethyl)-3,3-difluorocyclobutane.

Introduction

Creating new chemical entities (NCE) for drug discovery drives organic and medicinal chemists to develop structural motifs with unique characteristics that improve physico-chemical properties of drug-like molecules.^[1] In this regard, the gem-difluoromethylene unit is of special interest^[2] since it can be considered as a lipophilic bioisostere of carbonyl and many other groups.^[3] Introducing the CF₂ unit into sp³-enriched carbo- and heterocycles makes them useful scaffolds for medicinal chemistry,^[4] which is confirmed by structures of FDA-approved marketed drugs Maraviroc (1),^[5] aselective inhibitor of chemokine receptor CCR5 with anti-HIV-1 activity, and Ivosidenib (2) usedto treat acute myeloid leukemia (Figure 1).^[6]

Figure 1.

gem-Difluocycloalkanes – marketed drugs.

Another trend driven by drug discovery is exploiting spiro scaffolds for fine-tuning pharmacodynamic and pharmacokinetic parametersof the parent molecule during optimization.^[7] In this view, 2,5- and 2,6-functionalized spiro[3.3]heptane derivatives have been considered as structural isosteres and conformationally restricted surrogates of 1,3- or 1,4-substituted cyclo hexanes, respectively (Figure 2a).^[8] Moreover, a series of heteroatom-substituted azaspiro[3.3]heptanes were designed as restricted surrogates of piperidine, piperazine, morpholine, or thiomorpholine derivatives (Figure 2).^[9] Further biological evaluation have revealed that replacement of six-membered monocyclic unit in a lead molecule with the corresponding spiro[3.3]heptane analog significantly improves its pharmacological profile.^[9b] Specifically, the modified molecule retains its biological activity amid increased aqueous solubility and metabolic stability, while lipophilicity is reduced.

Figure 2.

Spirocyclic analogues of saturated carbo- and heterocyclic six-membered rings.

In line with the above discussion, we have turned our attention to 6,6-difluorospiro[3.3]heptane building blocks, that might be used as surrogates of gem-difluorocycloalkanes (including 4,4-difluorocyclohexane and 3,3-difluorocyclobutane derivatives like those shown in Figure 1). Previously we have disclosed synthesis of 6,6-difluorospiro[3.3]heptan-2-amine and 6,6-difluorospiro[3.3]heptane-2-carboxylic acid trough the consecutive synthesis strategy.^[10] Both compounds were obtained from the corresponding ester, in turn prepared by deoxofluorination of methyl 6-oxospiro[3.3]heptane-2-carboxylate – a product of a seven-step reaction sequence (Scheme 1).The major drawback of this method was its poor scalability and limited diversity of the functionalized derivatives that could be prepared.

Scheme 1.

Retrosynthetic disconnection of 6,6-difluorospiro[3.3]heptane-containing building blocks.

The present work is aimed at developing an alternative approach for the preparation of numerous 6,6-difluorospiro[3.3]heptane-containing building blocks, based on more efficient convergent synthetic strategy. In this regard, 1,1-bis(bromomethyl)-3,3-difluorocyclobutane (3) was envisaged as the key synthetic precursor to obtain all the target derivatives. Compound 3 can be synthesized from dialkyl 3,3-difluorocyclobutane-1,1-dicarboxylate, which should be accessible by deoxofluorination of the corresponding cyclobutanone derivative 4. Preparation of compound 4 is well-documented in the literature and commences from alkylation of diisopropylmalonate with 1,3-dibromo-2,2-dimethoxypropane.^[11]

Results and Discussion

We initiated our study with synthesis of the key precursor 3. In this way, diisopropyl 3-oxocyclobutane-1,1-dicarboxylate (4), was deoxofluorinated with Morph-DAST to give 3,3-difluorocyclobutane-containing diester 5 (65%). This product smoothly reacted with LiAlH₄ affording dialcohol 6 (94%). Further modified Appel reaction^[12] afforded the target dibromide 3 in 64% Yield Scheme 2).Notably, nearly 600 g of this key precursor could be obtained from a single run of the latter step.

Scheme 2.

The synthesis of the key precursor 3.

With large quantities of compound 3 in hands, we could prepare several common synthetic intermediates bearing the 6,6-difluorospiro[3.3]heptane scaffold by double alkylation of the corresponding active methylene compounds (Scheme 3). Particularly, the NaH-mediated alkylation of diethyl malonate afforded diester 7 (88% yield, 472 g), while reaction with ethyl cyanoacetate in the presence of K₂CO₃ as a base gave cyano ester 8 (68% yield, 221 g). Finally, NaH-mediated alkylation of tosylmethyl isocyanide (TosMIC) followed by hydrolysis of the intermediate isonitrile 9 led to ketone 10 (45% yield over two steps).The subsequent reduction of ketone 10 with LiAlH₄ led to the corresponding alcohol 11 (92% yield, 18.6 g).

Scheme 3.

The synthesis of common synthetic intermediates.

Saponification of diester 7 under mild conditions (NaOH, aq. EtOH, rt, 12 h), followed by thermal pyridine-mediated decarboxylation of product 12 allowed for the preparation ofcarboxylic acid 13 in 87% overall Yield Scheme 4). The latter appeared to be another supremely versatile synthetic intermediate for preparation of the target building blocks.

Scheme 4.

Synthesis of carboxylic acid 13.

First of all, carboxylic acid 13 was converted to amide 14 (95% yield) under typical conditions (oxalyl chloride in CH₂Cl₂, followed by NH₃ in THF at 0 °C). In turn, LiAlH₄-mediated reduction of 14 yielded primary amine 15 (79% yield, 36 g, isolated as hydrochloride).

Compound acid 13 was also the entry point for the route to homologous sulfonyl chlorides 16 and 17 (Scheme 6). Particularly, Barton decarboxylative bromination^[13] of 13 produced bromide 18 (60% yield, 90 g), which was involved into the nucleophilic substitution with AcS⁻ anionresulting in thioacetate 19 (91% yield). Ultimately, oxidative chlorination of 19 proceeded in a straightforward manner under typical conditions (Cl₂, CH₂Cl₂, water, 0 °C), and target sulfonyl chloride16 was obtained in 90% yield, 16 g (Scheme 6).

Scheme 6.

Synthesis of homologous sulfonyl cholrides 16 and 17.

Approach to another sulfonyl chloride 17 involved reduction of acid 13 with LiAlH₄ giving alcohol 20 (79% yield), which was transformed into bromide 21 (76% yield) upon the modified Appel reaction conditions. The latter steps were similar to those described above and allowed for the preparation of thioacetate 22 (87% yield) and sulfonyl cholride 17 (72% yield, 53 g).

The synthetic utility of bromide 18 was also demonstrated by preparation of two novel organoboron reagents for the cross–coupling reactions.^[14] Thus, treatment of 18 with bis(pinacolato)diboron in the presence ofCu(PPh₃)Br and t-BuOLi afforded pinacolate 23 (76% yield, 50 g). In turn, compound 23 reacted with KHF₂ in aq. MeOH to give the corresponding trifluoroborate 24 in 79% yield, 36.6 g (Scheme 7).

Scheme 7.

Synthesis of organoboron derivatives 23 and 24.

In addition, alcohol 20 was subjected to the Swern oxidation^[15] to give aldehyde 25 (90% yield, 36 g). The subsequent Seyferth – Gilbert homologation^[16] of 25 with the Ohira – Bestmann reagent^[17] provided corresponding alkyne 26, which was isolated in 76% yield, 30 g (Scheme 8).

Scheme 8.

Synthesis of aldehyde 25 and alkyne 26.

Finally, synthesis of two homologous amino acids 27 and 28 (as well as their derivatives) bearing the 6,6-difluorospiro[3.3]heptane backbonewas envisioned (Schemes 9 and 10). In this way, diester 7 was saponified with an equimolar amount of NaOH to afford semiester 29 (81%). Further modified Curtius rearrangement of the corresponding acyl azide allowed for the preparation of Boc-protected α-amino ester 30 (71%). The latter was converted into amino ester 31 (80% yield, trifluoroacetate) and Boc-protected amino acid 32 (85% yield) through the cleavage of the corresponding protective groups. Derivative 32 was processed into the target α-amino acid 27 (95% yield, 18.6 g) upon reflux in aqueous media (Scheme 9).

Scheme 9.

The synthesis of α-amino acid 27and its derivatives.

Scheme 10.

The synthesis of β-amino acid 28 and its derivatives.

The structure of Boc-protected amino acid 32 was confirmed by X-ray diffraction studies (Figure 3).

Figure 3.

Molecular structure of compound 32 according to X-ray diffraction study.

Synthesis of β-amino acid 28 included the Raney Ni-catalyzed hydrogenation of cyano ester 8 in the presence of Boc₂O, that gave Boc-protected β-amino acid ester 33 in 87% yield. The further steps were similar to those described above for 27. Thus, saponification of 33 yielded the N-Boc derivative 34 (84% yield) while further heating in aqueous media led to desired β-amino acid 28 (96% yield). Meanwhile, compound 34 was converted into the corresponding amino acid ester 35 (88% yield, 19.4 g, as hydrochloride) when treated with 2 M ethanolic HCl (Scheme 10). Finally, amino alcohol 36 was obtained by reduction of cyano ester 8 with LiAlH₄ in THF media (70% yield, 27.8 g as hydrochloride).

Conclusions

A convenient methodology to construct 6,6-difluorospiro[3.3]heptane scaffold was developed. The strategy was convergent and relied on double alkylation of the corresponding 1,1-binucleophiles with 1,1-bis(bromomethyl)-3,3-difluorocyclobutane. This allowed preparation of a diverse set of hereto unknown mono- and bifunctional 6,6-difluorospiro[3.3]heptane derivatives – conformationally restricted surrogates of appropriately functionalized gem-difluorocycloalkanes (first of all, 4,4-difluorocyclohexanes and 3,3-difluorocyclobutanes with confirmed medicinal relevance) All the intermediates as well as the target compounds were prepared using relatively short reaction sequences on multigram scale (at least 10 g; up to 0.47 kg). Results of this study enable wide applications of 6,6-difluorospiro[3.3]heptanes as promisind lead-oriented building blocks for drug discovery^[18] and organic synthesis.

Experimental Section

The solvents were purified according to the standard procedures.^[19] All the starting materials were obtained from Enamine Ltd. and UORSY. Melting points were measured on MPA100 OptiMelt automated melting point system. Analytical TLC was performed using Polychrom SI F254 plates. ¹H, ¹³C{¹H}, ¹⁹F, and ¹¹B NMR spectra were recorded on a Agilent ProPulse 600 spectrometer (at 600 MHz for ¹H NMR and 151 MHz for ¹³C NMR), a Bruker 170 Avance 500 spectrometer (at 500 MHz for ¹H, 126 MHz for ¹³C, 470 MHz for ¹⁹F, and 160.4 MHz for ¹¹B), or a Varian Unity Plus 400 spectrometer (at 400 MHz for ¹H, 101 MHz for ¹³C, and 376 MHz for ¹⁹F). Chemical shifts are reported in ppm downfield from TMS as an internal standard. Elemental analyses were performed on a CHNOS elementary Vario MICRO Cube analyzer. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument (chemical ionization (APCI)) and Agilent 5890 Series II 5972 GCMS instrument (electron impact ionization (EI)). CCDC deposition number for the structure of 32 is 1993871. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

Diisopropyl 3,3-difluorocyclobutane-1,1-dicarboxylate (5):

Diisopropyl 3-oxocyclobutane-1,1-dicarboxylate (4) (1.24 kg, 5.11 mol) was dissolved in CH₂Cl₂ (2 L) and the obtained solution was cooled to 0 °C. Then Morph-DAST (2.15 kg, 12.3 mol) was added portionwise at the same temperature. The reaction mixture was allowed to warm to rt and left to react with stirring for 48 h. Then it was slowly added to the stirred cold (0 °C) solution of Na₂CO₃ (5.25 kg, 49.5 mol) in water (20 L) over 0.5 h. The organic layer was separated, and the aqueous phase was extracted with CH₂Cl₂ (2×1.5 L). The combined organic layers were dried (Na₂SO₄) and evaporated at reduced pressure. The residue was distilled in vacuo to give the title compound 5 as colorless liquid. Yield 872 g, 65%; b.p. 96 °C (1 mBar); ¹H NMR (500 MHz, CDCl₃): δ = 5.09 (sept, J = 6.4 Hz, 2H), 3.11 (t, J = 11.9 Hz, 4H), 1.26 (d, J = 6.4 Hz, 12H) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 169.2, 117.4 (t, J = 276.5 Hz), 69.9, 42.7 (t, J = 25.6 Hz), 42.6, 21.6 ppm; ¹⁹F{¹H} NMR (470 MHz, CDCl₃): δ = −90.4 ppm; MS (APCI): m/z = 223 [M+H─C₃H₆]⁺; elemental analysis calcd. (%) for C₁₂H₁₈F₂O₄: C 54.54, H 6.87; found: C 54.23, H 6.72.

(3,3-Difluorocyclobutane-1,1-diyl)dimethanol (6):

Compound 5 (872 g, 3.30mol) was added dropwise to a stirred boiling suspension of LiAlH₄ (188 g, 4.95 mol) in THF (6.1 L), and the resulting mixture was allowed to stir at rt for 12 h. Then it was quenched by sequential dropwise addition of water (190 mL), 50% aq. NaOH (125 mL), and water (570 mL). The precipitate formed was filtered off, and the filtrate was evaporated at reduced pressure to give the title compound 6 as colorless needles. Yield 500 g,99.6%; m.p. 66–67 °C; ¹H NMR (400 MHz, CDCl₃): δ = 3.76 (s, 4H), 2.37 (t, J = 12.6 Hz, 4H), 2.35 (s, 2H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 119.2 (t, J = 279.4 Hz), 68.3 (t, J = 3.6 Hz), 39.9 (t, J = 22.8 Hz), 32.9 (t, J = 9.6 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −86.5 ppm; MS (EI): m/z = 114 [M─HF─H₂O]⁺; elemental analysis calcd. (%) for C₆H₁₀F₂O₂: C 47.37, H 6.63; found: C 47.30, H 6.30.

1,1-Bis(bromomethyl)-3,3-difluorocyclobutane (3):

PPh₃ (2.50kg, 9.53 mol) was dissolved in CH₂Cl₂ (5 L), and the obtained solution was cooled to 0 °C. Br₂ (490 mL, 1.52 kg, 9.49 mol) was added dropwise at the same temperature. The resulting mixture was additionally stirred at 0 °C for 1 h, then Et₃N (1.34 L, 973 g, 9.61 mol) was added dropwise maintaining the above temperature followed by additional stirring for 15 min. Next, a solution of 6 (500 g, 3.286 mol) in CH₂Cl₂ (1 L) was added dropwise at 0 °C, and the reaction mixture was allowed to warm to rt and left to react with stirring overnight. Then it was extracted with water (1 L) and 15% aq.Na₂CO₃ (1L). The organic layer was dried (Na₂SO₄) and evaporated at reduced pressure. The remainder was triturated with hexane (5 L) and filtered. The filtrate was evaporated at reduced pressure, and the residue was distilled in vacuo to give the title compound 3 as colorless liquid. Yield 590 g, 64%; b.p. 45 °C (1 mBar); ¹H NMR (400 MHz, CDCl₃): δ = 3.68 (s, 4H), 2.55 (t, J = 12.2 Hz, 4H) ppm;¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 116.70 (t, J = 278.1 Hz), 43.52 (t, J = 23.6 Hz), 39.30 (t, J = 4.3 Hz), 34.08 (t, J = 10.8 Hz) ppm;¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −88.8 ppm;MS (EI): m/z = 214 [M─CF₂=CH₂]⁺;elemental analysis calcd. (%) for C₆H₈Br₂F₂: C 25.93, H 2.90; found: C 26.03, H 3.01.

Diethyl 6,6-difluorospiro[3.3]heptane-2,2-dicarboxylate (7):

Diethyl malonate (650 g, 4.06 mol) was added dropwise to a cold (0 °C) stirred suspension of NaH (60% dispersion in mineral oil, 154.6 g, 3.87 mol) in DMF (2.7 L) while the above temperature was maintained. The obtained mixture was slowly heated to 60 °C, and compound 3 (538 g, 1.94mol) was added dropwise. The reaction mixture was slowly heated to 120 °C and stirred at this temperature for 12h. Then it was cooled to rt, diluted with water (4 L) and extracted with EtOAc (3×1.5 L). The combined extracts were washed with water (3×3 L), dried (Na₂SO₄) and evaporated at reduced pressure. The residue was distilled in vacuo affording the title compound 7 as colorless liquid. Yield 472 g, 88%; b.p. 95 °C (1 mBar); ¹H NMR (400 MHz, CDCl₃): δ = 4.21–4.16 (m, 4H), 2.65 (t, J = 2.6 Hz, 4H), 2.58 (tt, J = 12.2, 2.6 Hz, 4H), 1.28–1.16 (m, 6H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 171.3, 119.0 (t, J = 279.0 Hz), 61.6, 48.5, 47.6 (t, J = 22.3 Hz), 40.3, 27.3 (t, J = 9.6 Hz), 14.0 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −92.0 ppm; MS (EI): m/z = 276 [M]⁺; elemental analysis calcd. (%) for C₁₃H₁₈F₂O₄: C 56.52, H 6.57; found: C 56.88, H 6.41.

Ethyl 2-cyano-6,6-difluorospiro[3.3]heptane-2-carboxylate (8):

Compound 3 (391 g, 1.42 mol) was dissolved in DMF (1.95 L) followed by addition of ethyl 2-cyanoacetate (240 g, 2.12 mol) and K₂CO₃ (582 g, 4.22 mol). The resulting mixture was heated to 80 °C and stirred at this temperature for 12 h. Then it was cooled to rt, diluted with water (3L) and extracted with EtOAc (3×1000 mL). The combined organic layer was washed with water (3×200 mL), dried (Na₂SO₄) and evaporated at reduced pressure. The residue was distilled in vacuo to give the title compound 8 as colorless liquid. Yield 221 g, 68%; b.p. 90 °C (1 mBar); ¹H NMR (400 MHz, CDCl₃): δ = 4.24 (q, J = 7.1 Hz, 2H), 2.86–2.79 (m, 2H), 2.79–2.68 (m, 4H), 2.63 (td, J = 12.1, 2.9 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 168.2, 119.6, 118.5 (t, J = 278.5 Hz), 63.1, 47.7 (t, J = 22.8 Hz), 47.4 (t, J = 22.8 Hz), 42.4 (t, J = 2.3 Hz), 35.5, 28.6 (t, J = 9.8 Hz), 13.9 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −92.2 ppm; MS (EI): m/z = 229 [M]⁺; elemental analysis calcd. (%) for C₁₁H₁₃F₂NO₂: C 57.64, H 5.72, N 6.11; found: C 57.66, H, 5.93, N, 6.03.

6,6-Difluorospiro[3.3]heptan-2-one (10):

Compound 3 (105 g, 378 mmol) was dissolved in Et₂O (1 L) followed by addition of NaH (60% dispersion in mineral oil, 52.8 g, 1.32 mol). Then the solution of TosMIC (200 g, 1.02 mol) in DMSO (1 L) was added dropwise upon stirring at rt. The resulting suspension was stirred at the same temperature for 2 h, poured into water (2.4 L), and extracted with EtOAc (3×900 mL). The combined organic layer was dried (MgSO₄) and evaporated at reduced pressure affording the crude compound 9, which was dissolved in Et₂O (750 mL) followed by addition of 12 M aq. HCl (300 mL). The resulting mixture was stirred at rt for 16 h, diluted with water (900mL) and extracted with Et₂O (3×400 mL). The combined organic layer was dried (Na₂SO₄) and evaporated at reduced pressure. The residue was distilled in vacuo to give the title compound 10 as colorless liquid. Yield 25.0 g, 45%; b.p. 66 °C (7 mBar); ¹H NMR (400 MHz, CDCl₃): δ = 3.24 (s, 4H), 2.82 (t, J = 11.9 Hz, 4H) ppm; ¹³C{¹H} NMR (126 MHz, Cl₃): δ = 204.7, 118.6 (t, J = 278.5 Hz), 58.5 (t, J = 2.7 Hz), 46.7 (t, J = 22.9 Hz), 22.7 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −93.2 ppm; MS (EI): m/z = 146 [M]⁺; elemental analysis calcd.(%) for C₇H₈F₂O: C 57.53, H 5.52; found: C 57.80, H, 5.18.

6,6-Difluorospiro[3.3]heptan-2-ol (11):

Compound 10 (20.0g, 0.14mol) was added dropwise to the stirred cold (0 °C) suspension of LiAlH₄ (3.64 g, 0.10mol) in THF (150 mL) and the resulting mixture was allowed to equilibrate to rt and stirred for 3 h. Then it was quenched by sequential dropwise addition of water (4 mL), 50% aq. NaOH (2.7 mL), and water (10 mL) again, while the above temperature was maintained. The formed precipitate was filtered off and the filtrate was evaporated at reduced pressure to give the title compound 11 as yellowish liquid. Yield 18.6 g, 92%; ¹HNMR (400 MHz, CDCl₃): δ = 4.25 (p, J = 7.3 Hz, 1H), 2.54 (t, J = 12.3 Hz, 4H), 2.46 (ddd, J = 9.8, 7.3, 3.1 Hz, 2H), 2.06 (ddd, J = 9.8, 7.3, 3.1 Hz, 2H), 1.78 (s, 1H) ppm; ¹³C{¹H}NMR (126 MHz, CDCl₃): δ = 119.7 (t, J = 279.6 Hz), 62.8, 47.2 (t, J = 21.9 Hz), 46.5 (t, J = 21.9 Hz), 44.7 (t, J = 2.0 Hz), 23.9 (t, J = 9.5 Hz) ppm; ¹⁹F{¹H}NMR (376 MHz, CDCl₃): δ = −91.6 ppm; MS (EI): m/z = 84 [M─CF₂CH₂]⁺; elemental analysis calcd. (%) for C₇H₁₀F₂O: C 56.75, H 6.80; found: C 57.04, H 7.04.

6,6-Difluorospiro[3.3]heptane-2,2-dicarboxylic acid (12):

Compound 7 (472 g, 1.71 mol) was dissolved in MeOH (1 L), and the resulting solution was added to the stirred solution of NaOH (272 g, 6.80 mol) in water (1 L). The reaction mixture was left to react with stirring at rt for 12 h. Then MeOH was evaporated at reduced pressure, the aqueous layer was extracted with t-BuOMe (500 mL), acidified with 10 M aq. HCl to pH = 3 and extracted with EtOAc (3×800 mL). The organic layer was dried (Na₂SO₄) and evaporated at reduced pressure to give the title compound 12 as colorless crystals. Yield 350 g, 94%; m.p. 190–191 °C; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.78 (s, 2H), 2.55 (t, J = 12.4 Hz, 6H), 2.46 (t, J = 1.9 Hz, 2H) ppm; ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ = 173.11, 120.37 (t, J = 278.6 Hz), 48.33, 47.27 (t, J = 21.3 Hz), 40.07, 27.09 (t, J = 9.5 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ = −89.9 ppm; MS (APCI): m/z = 219 [M─H]⁻; elemental analysis calcd. (%) for C₉H₁₀F₂O₄: C 49.10, H 4.58; found: C 49.25, H 4.25.

6,6-Difluorospiro[3.3]heptane-2-carboxylic acid(13):

Compound 12 (350 g, 1.59 mol) was dissolved in pyridine (2 L) and the resulting solution was refluxed for 12 h. Then it was evaporated at reduced pressure, the residue was diluted with water (1.5 L), acidified with 10 M aq. HCl to pH = 3 and extracted with EtOAc (3×600 mL). The combined organic layer was dried (Na₂SO₄) and evaporated at reduced pressure to give the title compound 13 as yellowish crystals. Yield 350 g, 93%; m.p. 46–47°C. For spectral data, see ref.^[4j]

6,6-Difluorospiro[3.3]heptane-2-carboxamide(14):

Compound 13 (42.0 g, 0.24 mol) was dissolved in CH₂Cl₂ (500 mL) followed by addition of DMF (1mL) and oxalyl chloride (46.0 g, 0.36 mol).The resulting mixture was stirred until gas evolution ceased (ca. 2 h),then it was evaporated at reduced pressure, the residue was dissolved in THF (500mL), and the resulting solution was cooled to 0 °C. After, gaseous NH₃ was bubbled through the stirred reaction mixture until pH reached 8–9. The precipitate formed was filtered off and the filtrate was evaporated at reduced pressure to give the title compound 14 as white crystals. Yield 40.1 g, 95%; m.p. 139–141 °C; ¹H NMR (400 MHz, DMSO-d₆): δ = 7.13 (s, 1H), 6.68 (s, 1H), 2.84 (p, J = 8.4 Hz, 1H), 2.58 (t, J = 12.6 Hz, 2H), 2.45–2.38 (m, 2H), 2.22–2.14 (m, 2H), 2.10 (t, J = 10.2 Hz, 2H) ppm; ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ = 175.9, 120.7 (t, J = 279.3 Hz), 47.3 (t, J = 21.2 Hz), 46.6 (t, J = 21.0 Hz), 36.5, 33.6, 28.7 (t, J = 9.3 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ = −89.6 ppm; MS (EI): m/z = 175 [M]⁺; elemental analysis calcd. (%) for C₈H₁₁F₂NO: C 54.85, H 6.33, N, 8.00; found: C 54.79, H 6.27, N, 8.13.

(6,6-Difluorospiro[3.3]heptan-2-yl)methanamine hydrochloride (15):

Compound 14 (40.0g, 0.23mol) was added portionwise to the stirred boiling suspension of LiAlH₄ (13.0 g, 0.34mol) in THF (500 mL), and the resulting mixture was refluxed with stirring for 2 h. Then it was cooled to rt and quenched by sequential dropwise addition of water (13 mL), 50% aq. NaOH (8.7 mL), and water (40 mL). The precipitate was filtered off and the filtrate was evaporated at reduced pressure. The residue was dissolved in Et₂O (200mL) followed by addition of 4M HCl in Et₂O (40mL). The precipitate formed was filtered to give the title compound 15 as white powder. Yield 36.0 g, 79%; m.p. 186–188 °C; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.01 (s, 3H), 2.79 (d, J = 7.5 Hz, 2H), 2.61 (t, J = 12.5 Hz, 2H), 2.54 (d, J = 12.5 Hz, 2H), 2.47–2.39 (m, 1H), 2.17 (ddd, J = 10.4, 8.1, 2.1 Hz, 2H), 1.93 (ddd, J = 10.4, 8.1, 2.1 Hz, 2H) ppm; ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ = 120.7 (t, J = 279.5 Hz), 47.4 (t, J = 21.1 Hz), 46.8 (t, J = 21.1 Hz), 43.9, 37.2, 28.6 (t, J = 9.0 Hz), 27.8 ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ = −89.5 ppm; MS (APCI): m/z = 162 [M+H]⁺; elemental analysis calcd. (%) for C₈H₁₄ClF₂N: C 48.62, H 7.14, N 7.09; found: C 48.98, H 7.39, N 7.24.

6-Bromo-2,2-difluorospiro[3.3]heptane (18):

Compound 13 (125 g, 0.71 mol) and 1-hydroxypyridine-2(1H)-thione (90.2 g, 0.71 mol) were dissolved in CH₂Cl₂ (1L) and the resulting solution was cooled to 0 °C. DCC (153.6 g, 0.74 mol) was added portionwise at the same temperature and the reaction mixture was allowed to equilibrate to rt and stirred for 12 h. Then it was filtered and evaporated to ca. 10% of initial volume at reduced pressure. The solution thus obtained was added to the stirred solution of CBrCl₃ (704 g, 350 mL, 3.55 mol) in CH₂Cl₂ (200mL) and the stirred reaction mixture was irradiated with 100 W tungsten bulb for 2 h and left to stir for additional 12 h. Then it was evaporated at reduced pressure, the residue was distilled in vacuo to give the title compound 18 as colorless liquid. Yield 90.3 g, 60%; b.p. 60 °C (7 mBar); ¹H NMR (400 MHz, CDCl₃): δ = 4.35 (p, J = 7.5 Hz, 1H), 2.77 (ddd, J = 10.5, 7.5, 3.1 Hz, 2H), 2.67–2.54 (m, 6H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 119.2 (t, J = 279.5 Hz), 47.1 (t, J = 22.7 Hz), 47.0 (t, J = 22.7 Hz), 46.5, 36.6, 29.8 (t, J = 9.6 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −91.8 ppm;MS (EI): m/z = 131 [M─Br]⁺; elemental analysis calcd. (%) for C₇H₉BrF₂: C 39.84, H 4.30; found: C 39.61, H 4.24.

(6,6-Difluorospiro[3.3]heptan-2-yl)methanol (20):

Compound 13 (90 g, 0.51 mol) was added portionwise to the stirred boiling suspension of LiAlH₄ (31 g, 0.82 mol) in THF (1.2 L) and the resulting mixture was allowed to stir at rt for 12 h. Then it was quenched by sequential dropwise addition of water (30 mL), 50% aq. NaOH (20 mL), and water (90 mL) again. The formed precipitate was filtered off and the filtrate was evaporated at reduced pressure. The residue was distilled in vacuo to give the title compound 20 as colorless liquid. Yield 65 g, 79%; b.p. 59 °C (1 mBar); ¹H NMR (400 MHz, CDCl₃): δ = 3.57 (t, J = 5.3 Hz, 2H), 2.57 (t, J = 12.3 Hz, 2H), 2.47 (t, J = 12.3 Hz, 2H), 2.45–2.35 (m, 1H), 2.16 (dd, J = 12.3, 8.0 Hz, 2H), 1.90 (dd, J = 12.3, 8.0 Hz, 2H), 1.30 (t, J = 5.3 Hz, 1H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 119.7 (t, J = 279.7 Hz), 66.7, 47.9 (t, J = 21.6 Hz), 47.3 (t, J = 21.6 Hz), 36.3, 31.7, 28.7 (t, J = 8.8 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −91.5 ppm; MS (EI): m/z = 162 [M]⁺; elemental analysis calcd. (%) for C₈H₁₂F₂O: C 59.25, H 7.46; found: C 59.36, H 7.43.

6-(Bromomethyl)-2,2-difluorospiro[3.3]heptane (21):

PPh₃ (81.0 g, 0.31 mol) was dissolved in CH₂Cl₂ (400 mL) and the obtained solution was cooled to 0 °C followed by dropwise addition of Br₂ (15.8 mL, 49.0 g, 0.31 mol) at the same temperature. The resulting mixture was additionally stirred at 0 °C for 1 h, then Et₃N (43 mL, 31.2 g, 0.31 mol) was added dropwise maintaining the above temperature followed by additional stirring for 15 min. After, the solution of 20 (40g,0.25 mol) in CH₂Cl₂ (100 mL) was added dropwise at 0 °C.The reaction mixture was allowed to equilibrate to rt and left to react with stirring overnight. Then it was subsequently extracted with water (1×100 mL) and 15% aq. Na₂CO₃ (1×100 mL). The organic layer was dried (Na₂SO₄) and evaporated at reduced pressure. The remainder was dispersed in hexane (1L) and filtered. The filtrate was evaporated at reduced pressure and the residue was distilled in vacuo to give the title compound 21 as colorless liquid. Yield 43 g, 76%; b.p. 47 °C (1 mBar); ¹H NMR (400 MHz, CDCl₃): δ = 3.38 (d, J = 7.3 Hz, 2H), 2.69–2.61 (m, 1H), 2.58 (t, J = 11.5 Hz, 2H), 2.49 (t, J = 12.3 Hz, 2H), 2.24 (dd, J = 12.3, 8.2 Hz, 2H), 1.89 (dd, J = 12.3, 8.2 Hz, 2H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 119.5 (t, J = 279.7 Hz), 47.8 (t, J = 21.8 Hz), 47.0 (t, J = 21.8 Hz), 39.0, 38.5, 32.1, 27.5 (t, J = 8.7 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −91.6 ppm; MS (EI): m/z = 125 [M─HF─Br]⁺; elemental analysis calcd. (%) for C₈H₁₁BrF₂: C 42.69, H 4.93; found: C 43.09, H 5.09.

General Procedure for the Preparation of Ethanethioates 19 and 22:

The corresponding bromide 18, 21 (0.17 mol) was dissolved in DMF (175 mL), then KSAc (28.3 g, 0.25 mol) was added and the resulting mixture was stirred at 50 °C for 12 h. Then it was diluted with water (400mL) and extracted with t-BuOMe (2×300 mL). The organic layer was washed with water (3×100 mL), dried (Na₂SO₄), and evaporated at reduced pressure to give title compound 19, 22.

S-(6,6-Difluorospiro[3.3]heptan-2-yl) ethanethioate (19):

from 18 (35.0 g, 0.17 mol), brown liquid (31.2 g, 91%; ¹H NMR (500 MHz, CDCl₃): δ = 3.98 (p, J = 8.2 Hz, 1H), 2.65 (t, J = 12.6 Hz, 2H), 2.61–2.57 (m, 2H), 2.57–2.51 (m, 2H), 2.28 (s, 3H), 2.18 (ddd, J = 12.6, 6.3, 2.2 Hz, 2H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 195.6, 119.6 (t, J = 279.8 Hz), 47.3 (t, J = 22.1 Hz), 47.0 (t, J = 22.1 Hz), 41.6 (t, J = 2.1 Hz), 31.7, 30.4, 29.8 (t, J = 9.2 Hz) ppm; ¹⁹F{¹H} NMR (470 MHz, CDCl₃): δ = −91.3 ppm; MS (EI): m/z = 206 [M]⁺; elemental analysis calcd. (%) for C₉H₁₂F₂OS: C 52.41, H 5.86, S 15.54; found: C 52.29, H 6.08, S 15.32.

S-((6,6-Difluorospiro[3.3]heptan-2-yl)methyl) ethanethioate (22):

from 21 (76.7 g, 0.34 mo) and KSAc (55.6 g, 0.49 mol), brown liquid (65.0 g, 87%; ¹H NMR (400 MHz, CDCl₃): δ = 2.91 (d, J = 7.4 Hz, 2H), 2.54 (t, J = 12.4 Hz, 2H), 2.47 (t, J = 12.5 Hz, 2H), 2.42 – 2.33 (m, 1H), 2.31 (s, 3H), 2.22 – 2.13 (m, 2H), 1.86 – 1.75 (m, 2H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 195.7, 119.6 (t, J = 279.8 Hz), 47.7 (t, J = 21.7 Hz), 46.9 (t, J= 21.7 Hz), 39.2 (t, J = 1.7 Hz), 34.7, 30.6, 29.7, 28.2 (t, J = 8.9 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −91.5 ppm; MS (EI): m/z = 177 [M─CH₃CO]⁺; elemental analysis calcd. (%) for C₁₀H₁₄F₂OS: C 54.53, H 6.41, S 14.55; found: C 54.65, H 6.39, S 14.59.

General Procedure for the Preparation of sulfonyl chlorides 16 and 17:

The corresponding ethanethioate19, 22(0.15 mol) was dissolved in CH₂Cl₂ (300 mL), then water (300 mL) was added, and the resulting mixture was cooled to 0 °C. After, Cl₂ was bubbled through the stirred reaction mixture until it became yellow green. The layers were separated, the organic phase was washed with water (2×100 mL), dried (Na₂SO₄) and evaporated at reduced pressure to give the title compound16, 17.

6,6-Difluorospiro[3.3]heptane-2-sulfonyl chloride (16):

from 19 (31.0 g, 0.15 mol), yellowish crystals (31.1 g, 90%), m.p. 42–44 °C; ¹H NMR (400 MHz, CDCl₃): δ = 4.33 (p, J = 7.9 Hz, 1H), 2.84 (dd, J = 14.0, 7.9 Hz, 2H), 2.73–2.61 (m, 6H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 118.3 (t, J = 278.8 Hz), 62.7, 47.4 (t, J = 22.7 Hz), 47.3 (t, J = 22.7 Hz), 36.5, 27.8 (t, J = 9.8 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −92.2 ppm;MS (APCI): m/z = 211 [M─H]⁻ (for the corresponding sulfonic acid); elemental analysis calcd. (%) for C₇H₉ClF₂O₂S: C 36.45, H 3.93, S 13.90; found: C 36.69, H 4.00, S 13.93.

(6,6-Difluorospiro[3.3]heptan-2-yl)methanesulfonyl chloride (17):

from 22 (65.0 g, 0.30 mol), yellowish oil (53.0 g, 72%; ¹H NMR (400 MHz, CDCl₃): δ = 3.74 (d, J = 7.3 Hz, 2H), 2.96 (p, J = 8.3 Hz, 1H), 2.66 (t, J = 11.9 Hz, 2H), 2.51 (t, J = 12.9 Hz, 2H), 2.43 (t, J = 9.5 Hz, 2H), 2.09 (dd, J = 12.9, 9.5 Hz, 2H) ppm; ¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 119.1 (t, J = 279.5 Hz), 70.3, 47.5 (t, J = 22.1 Hz), 46.5 (t, J = 22.1 Hz), 39.3, 29.5 (t, J = 9.1 Hz), 25.6 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −91.7 ppm; MS (APCI): m/z = 225 [M─H]⁻ (for the corresponding sulfonic acid); elemental analysis calcd. (%) for C₈H₁₁ClF₂O₂S: C 39.27, H 4.53, S 13.10; found: C 39.02, H 4.72, S 12.88.

2-(6,6-Difluorospiro[3.3]heptan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23):

The solution of compound 18 (53.5 g, 0.25 mol) in DMF (540 mL) was added dropwise to the stirred solid mixture of CuBr (3.64 g, 25.3 mmol), PPh₃ (8.65 g, 33.0 mmol), t-BuOLi (40.6 g, 0.51 mol), and (BPin)₂ (96.6 g, 0.38 mol) under Ar atmosphere, while maintaining internal temperature below 60 °C (Caution: Exothermic reaction!). The resulting mixture was stirred at rt for 12 h. Then it was diluted with EtOAc (1.2L) and filtered through silica gel. The filtrate was washed with water (1×500 mL and 2×300 mL), dried (Na₂SO₄) and evaporated at reduced pressure. The residue was dissolved in hexane (100 mL) and subjected to silica gel flash chromatography, using hexane (1 L) as eluent. The eluate was evaporated at reduced pressure to give the title compound 23 as colorless liquid. Yield 50.0g, 76%; ¹H NMR (500 MHz, CDCl₃): δ = 2.52 (q, J = 12.9 Hz, 4H), 2.20 (t, J = 9.5 Hz, 2H), 2.16–2.08 (m, 2H), 1.79 (p, J = 9.5 Hz, 1H), 1.24 (s, 12H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 119.9 (t, J = 280.0 Hz), 83.2, 47.5 (t, J = 21.4 Hz), 47.4 (t, J = 21.4 Hz), 35.5, 32.0 (t, J = 8.5 Hz), 29.7, 24.7 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −91.4 ppm; ¹¹B NMR (160 MHz, CDCl₃): δ = 33.9 ppm; MS (EI): m/z = 258 [M]⁺; elemental analysis calcd. (%) for C₁₃H₂₁BF₂O₂: C 60.49, H 8.20; found: C 60.55, H 8.35.

Potassium (6,6-difluorospiro[3.3]heptan-2-yl)trifluoroborate (24):

Compound 23 (50.0 g, 0.19 mol) was dissolved in MeOH (400 mL), then the solution of KHF₂ (91.0 g, 1.17 mol) in water (200 mL) was added in one portion and the resulting mixture was stirred at rt for 12 h. Then it was evaporated to dryness at reduced pressure, the remainder was triturated with MeCN (1 L) and filtered. The filtrate was evaporated to dryness at reduced pressure and the residue was dispersed in t-BuOMe (300 mL). The filtration afforded the title compound 24 as white crystals. Yield 36.6 g, 79%; m.p. 248–250 °C; ¹H NMR (400 MHz, DMSO-d₆): δ = 2.44 (t, J = 12.9 Hz, 2H), 2.33 (t, J = 12.9 Hz, 2H), 1.79 (p, J = 10.3 Hz, 4H), 1.11–0.97 (m, 1H) ppm; ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ = 121.5 (t, J = 280.6 Hz), 48.4 (t, J = 20.0 Hz), 47.6 (t, J = 20.0 Hz), 36.1, 30.8 (t, J = 7.8 Hz), 25.4 ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ = −88.79 (2F), −144.48 (3F) ppm; ¹¹B NMR (160 MHz, DMSO-d₆): δ = 4.31 ppm; elemental analysis calcd. (%) for C₇H₉BF₅K: C 35.32, H, 3.81; found: C 35.06, H 4.14.

6,6-Difluorospiro[3.3]heptane-2-carbaldehyde (25):

DMSO (46.2 g, 0.59 mol) was dissolved in CH₂Cl₂ (800 mL) and the resulting solution was cooled to −78 °C. Then oxalyl chloride (37.6, 0.30 mol) was added dropwise, and the resulting mixture was stirred at above temperature until gas evolution ceased (ca. 30min). After, compound 20 (40.0 g, 0.25 mol) was added dropwise and the reaction mixture was stirred at −78 °C for 30 min followed by dropwise addition of Et₃N (100 g, 138 mL, 0.99 mol) at −50 °C. The resulting mixture was allowed to warm to 0 °C and extracted with water (3×150 mL). The organic layer was dried (Na₂SO₄), and evaporated at reduced pressure to give the title compound 25 as yellowish liquid. Yield 36.3 g, 90%; ¹H NMR (400 MHz, CDCl₃): δ = 9.69 (s, 1H), 3.11 (p, J = 7.3 Hz, 1H), 2.59 (t, J = 10.7 Hz, 2H), 2.47 (t, J = 12.2 Hz, 2H), 2.42–2.33 (m, 2H), 2.26 (t, J = 10.7 Hz, 2H) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 201.5, 119.1 (t, J = 279.4 Hz), 47.6 (t, J = 22.0 Hz), 47.1 (t, J = 22.0 Hz), 40.3, 33.8 (t, J = 2.2 Hz), 29.3 (t, J = 9.2 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −91.8 ppm; MS (EI): m/z = 160 [M]⁺; elemental analysis calcd. (%) for C₈H₁₀F₂O: C 59.99, H 6.29; found: C 60.34, H 6.39.

6-Ethynyl-2,2-difluorospiro[3.3]heptane (26):

Compound 25 (40.0 g, 0.25 mol) and the Ohira – Bestmann reagent (57.6 g, 0.30 mol) were dissolved in MeOH (300 mL), then K₂CO₃ (103.4 g, 0.75 mol) was added portionwise. The reaction mixture was stirred at rt for 1.5 h, diluted with water (1.5 L) and extracted with hexane (4×250 mL). The organic layer was separated, dried (Na₂SO₄), and evaporated at reduced pressure. The residue was distilled in vacuo to give the title compound 26 as colorless liquid. Yield 29.8 g, 76%; b.p. 57 °C (37 mBar); ¹H NMR (400 MHz, CDCl₃): δ = 2.96 (pd, J = 8.3, 2.3 Hz, 1H), 2.59 (t, J = 12.2 Hz, 4H), 2.44 (td, J = 9.2, 8.3, 2.1 Hz, 2H), 2.28 (td, J = 9.2, 8.3, 2.3 Hz, 2H), 2.17 (d, J = 2.3 Hz, 1H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 119.4 (t, J = 279.6 Hz), 87.3, 69.2, 47.3 (t, J = 22.0 Hz), 47.0 (t, J = 22.0 Hz), 40.9 (t, J = 2.0 Hz), 29.8 (t, J = 9.2 Hz), 19.7 (t, J = 1.5 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −91.7 ppm; MS (EI): m/z = 156 [M]⁺; elemental analysis calcd. (%) for C₉H₁₀F₂: C 69.22, H 6.45; found: C 69.12, H, 6.49.

2-(Ethoxycarbonyl)-6,6-difluorospiro[3.3]heptane-2-carboxylic acid (29):

Compound 7 (287 g, 1.01 mol) was dissolved in EtOH (2 L) and brought to boil. Then a solution of NaOH (40.0 g, 1.0 mol) in water (800 mL) was added dropwise and the resulting solution was stirred and refluxed for 1 h. The reaction mixture was cooled to rt, EtOH was evaporated at reduced pressure, the remaining aqueous layer was extracted with t-BuOMe (1×200 mL) and acidified with 20% aq. NaHSO₄ to pH 2. Then it was extracted with EtOAc (3×300 mL), the combined organic layers were dried (Na₂SO₄) and evaporated at reduced pressure to give the title compound 29 as colorless liquid. Yield 200 g, 81%; ¹H NMR (400 MHz, CDCl₃): δ = 10.10 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.71 (s, 4H), 2.60 (td, J = 12.1, 2.7 Hz, 4H), 1.26 (t, J = 7.1 Hz, 3H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 177.0, 171.0, 118.9 (t, J = 278.8 Hz), 62.1, 48.4, 47.7 (t, J = 22.3 Hz), 47.6 (t, J = 22.3 Hz), 40.4, 27.3 (t, J = 9.6 Hz), 13.9 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −92.1 ppm; MS (APCI): m/z = 249 [M+H]⁺; elemental analysis calcd. (%) for C₁₁H₁₄F₂O₄: C 53.23, H 5.69; found: C 52.89, H 5.47.

Ethyl 2-((tert-butoxycarbonyl)amino)-6,6-difluorospiro[3.3]heptane-2-carboxylate (30):

Compound 29 (135 g, 0.54 mol) was dissolved in CH₂Cl₂ (1 L), and DMF (2.5 mL) and oxalyl chloride (90.0 g, 0.71 mol) were added dropwise. The resulting mixture was stirred until gas evolution ceased (ca. 2 h). Then it was evaporated at reduced pressure, the residue was dissolved in acetone (210 mL) and the obtained solution was added dropwise to cold (0 °C) stirred solution of NaN₃ (106 g, 1.63 mol) in water (320 mL). The reaction mixture was stirred at 0 °C for 1 h and extracted with EtOAc (2×300 mL). The combined organic layer was dried (Na₂SO₄) and evaporated to ½ of initial volume at reduced pressure. Thus obtained solution was added dropwise to the stirred hot (80 °C) mixture of PhMe (800 mL) and t-BuOH (400 mL). The resulting solution was refluxed with stirring for 12 h, cooled to rt, and evaporated at reduced pressure to give the title compound 29 as colorless needles. Yield 123 g, 71%; ¹H NMR (400 MHz, CDCl₃): δ = 5.16 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.69 (t, J = 12.6 Hz, 2H), 2.63 (t, J = 12.6 Hz, 2H), 2.64–2.43 (m, 4H),1.41 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 173.6, 154.7, 119.4 (t, J = 279.1 Hz), 61.6, 58.6, 54.3, 48.1 (t, J = 22.1 Hz), 48.0 (t, J = 22.1 Hz), 43.0, 28.3, 26.1 (t, J = 9.8 Hz), 14.1 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −92.0 ppm; MS (APCI): m/z = 220 [M─C₄H₈─CO₂+H]⁺; elemental analysis calcd. (%) for C₁₅H₂₃F₂NO₄: C 56.42, H 7.26, N 4.39; found: C 56.48, H 7.48, N 4.68.

Ethyl 2-amino-6,6-difluorospiro[3.3]heptane-2-carboxylate 2,2,2-trifluoroacetate (31):

Compound 30 (30.0 g, 93.9 mmol) was dissolved in CH₂Cl₂ (200 mL), then TFA (50 mL) was added and the resulting mixture was stirred at rt overnight. Then it was evaporated to dryness at reduced pressure, the residue was triturated with Et₂O (200 mL), and filtered to give the title compound 31 as white powder. Yield 25.0 g, 80%; m.p. 170 °C; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.61 (s, 3H), 4.23 (q, J = 7.1 Hz, 2H), 2.77 (t, J = 12.6 Hz, 2H), 2.70–2.54 (m, 6H), 1.27 (t, J = 7.1 Hz, 3H) ppm; ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ = 171.1, 158.7 (q, J = 31.2 Hz), 120.4 (t, J = 277.8 Hz), 117.6 (q, J = 299.7 Hz), 62.6, 52.9, 47.9 (t, J = 21.8 Hz), 47.1 (t, J = 21.7 Hz), 41.3, 25.8 (t, J = 10.2 Hz), 14.19 ppm; ¹⁹F{¹H}NMR (376 MHz, DMSO-d₆): δ = −74.1 (s, 3F), −90.3 (s, 2F) ppm; MS (APCI): m/z = 220 [M+H]⁺; elemental analysis calcd. (%) for C₁₂H₁₆F₅NO₄: C 43.25, H 4.84, N 4.20; found: C 43.28, H 4.98, N 4.52.

General Procedure for the Preparation of Boc-protected Amino Acids 32 and 34:

The solution of the correspondingBoc-protected ester30, 33(0.34 mol) in MeOH (800 mL) was added dropwise to the stirred solution of NaOH (54.0 g, 1.35 mol) in water (1 L) and the resulting mixture was stirred at rt for 12 h. MeOH was evaporated at reduced pressure, the remaining aqueous layer was extracted with t-BuOMe (1×300 mL) and acidified with 20% aq. NaHSO₄ to pH 3. Then it was extracted with EtOAc (3×400 mL), the combined organic layer was dried (Na₂SO₄), and evaporated at reduced pressure. The residue was recrystallized from t-BuOMe – hexane (1:1) affording the title compound 32, 34.

2-((tert-Butoxycarbonyl)amino)-6,6-difluorospiro[3.3]heptane-2-carboxylic acid (32):

from 30 (107 g, 0.34 mol),colorless crystals (83.2 g, 85%; m.p. 213–215 °C;the title compound was obtained as a ca. 1:2.5 mixture of rotamers; ¹H NMR (400 MHz, DMSO-d₆): δ = 12.35 (s, 1H), 7.50 and 7.22 (s, 1H), 2.67–2.53 (m, 6H), 2.28 (d, J = 12.3 Hz, 2H), 1.36 and 1.31 (s, 9H) ppm; ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ = 175.8 and 175.3, 155.2 and 154.7, 120.7 (t, J = 278.7 Hz), 78.6 and 78.5, 54.1 and 53.8, 47.7 (t, J = 20.8 Hz), 47.6 (t, J = 20.8 Hz), 47.4, 43.2 and 42.5, 28.7 and 28.4, 26.7 (t, J = 9.0 Hz) and 26.31 (t, J = 9.0 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO): δ = −89.8 ppm; MS (APCI): m/z = 290 [M─H]⁻; elemental analysis calcd. (%) for C₁₃H₁₉F₂NO₄: C 53.60, H 6.57, N 4.81; found: C 53.70, H 6.53, N 4.90.

General Procedure for the Preparation of Amino Acids 27 and 28:

The corresponding Boc-protected amino acid 32, 34 (0.10 mol) was suspended in water (600 mL) and the resulting mixture was stirred and refluxed for 14 h. Then it was cooled and evaporated to dryness at reduced pressure. The residue was triturated with MeCN (200 mL) and filtered to give the title compound 27, 28.

2-Amino-6,6-difluorospiro[3.3]heptane-2-carboxylic acid (27):

from 32 (30.0 g, 0.10 mol), white powder (18.6 g, 95%; m.p. 229–232 °C; ¹H NMR (400 MHz, D₂O): δ = 2.60 (dq, J = 26.7, 13.4 Hz, 6H), 2.40 (d, J = 13.4 Hz, 2H) ppm; ¹³C{¹H} NMR (151 MHz, D₂O): δ = 176.4, 120.2 (t, J = 277.9 Hz), 54.3, 47.1 (t, J = 22.2 Hz), 46.8 (d, J = 22.2 Hz), 41.0, 25.1 (t, J = 9.3 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, D₂O): δ = − 92.1 ppm; MS (APCI): m/z = 192 [M+H]⁺; elemental analysis calcd. (%) for C₈H₁₁F₂NO₂: C 50.26, H 5.80, N 7.33; found: C 50.56 H 5.71, N 7.43.

2-(Aminomethyl)-6,6-difluorospiro[3.3]heptane-2-carboxylic acid (28):

from 34 (30.0 g, 0.10 mol), white powder (19.4 g, 96%; m.p. 234–237 °C; ¹H NMR (400 MHz, D₂O): δ = 3.10 (s, 2H), 2.55 (td, J = 14.5, 12.7, 5.0 Hz, 4H), 2.44 (d, J = 12.7 Hz, 2H), 2.06 (d, J = 12.7 Hz, 2H) ppm; ¹³C{¹H} NMR (151 MHz, D₂O): δ = 181.8, 120.4 (t, J = 278.0 Hz), 47.1 (t, J = 22.4 Hz), 47.0 (t, J = 21.9 Hz), 45.5, 41.5, 39.6, 25.9 (t, J = 8.2 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, D₂O): δ = −91.3 ppm; MS (APCI): m/z = 206 [M+H]⁺; elemental analysis calcd. (%) for C₉H₁₃F₂NO₂: C 52.68, H 6.39, N 6.83; found: C 52.75 H 6.30, N 6.52.

Ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-6,6-difluorospiro[3.3]heptane-2-carboxylate (33):

Compound 8 (90.0 g, 0.39 mol) was dissolved in EtOH (400 mL) followed by addition of Boc₂O (119 g, 0.55 mol) and Raney-Ni (prepared from 22.5 g of Raney Ni─Al alloy). The resulting mixture was loaded in an autoclave and hydrogenated at 10 MPa and rt for 48 h. Then it was filtered and evaporated at reduced pressure to give the title compound 33 as colorless oil. Yield 113 g, 87%; ¹H NMR (400 MHz, CDCl₃): δ = 4.91 (s, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.42 (d, J = 6.2 Hz, 2H), 2.67 (t, J = 12.3 Hz, 2H), 2.60 (t, 12.3 Hz, 2H),2.49 (d, J = 12.3 Hz, 2H), 2.15 (d, J = 12.3 Hz, 2H), 1.42 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H) ppm; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 175.5, 156.3, 119.3 (t, J = 279.3 Hz), 79.4, 61.1, 48. 3 (t, J = 22.2 Hz), 48.1 (t, J = 22.2 Hz), 45.7, 43.3, 39.8, 28.3, 26.8 (t, J = 9.4 Hz), 14.2 ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −91.6 ppm; MS (APCI): m/z = 234 [M─C₄H₈─CO₂+H]⁺; elemental analysis calcd. (%) for C₁₆H₂₅F₂NO₄: C 57.65, H 7.56, N 4.20; found: C 57.81, H 7.32, N 4.14.

2-(((tert-Butoxycarbonyl)amino)methyl)-6,6-difluorospiro[3.3]heptane-2-carboxylic acid (34):

from 33 (113 g, 0.34 mol),colorless crystals (87.2 g, 84%; m.p. 139–140 °C;the title compound was obtained as a ca. 1:2.3 mixture of rotamers; ¹H NMR (400 MHz, CDCl₃): δ = 6.34 and 4.97 (s, 1H), 3.49–3.38 (m, 2H), 2.73–2.51 (m, 6H), 2.20 (d, J = 12.8 Hz) and 2.13 (d, J = 10.7 Hz, 1H), 1.48 and 1.42 (s, 9H) ppm; ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ = 177.0, 156.6, 120.5 (t, J = 278.9 Hz), 78.2, 47.7 (t, J = 20.5 Hz), 47.6 (d, J = 20.5 Hz), 45.3, 43.8, 39.1, 28.6, 26.2 (t, J = 9.2 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, CDCl₃): δ = −91.7 ppm;MS (APCI): m/z = 304 [M─H]⁻; elemental analysis calcd. (%) for C₁₄H₂₁F₂NO₄: C 55.07, H 6.93, N 4.59; found: C 54.69, H 6.95, N 4.19.

Ethyl 2-(aminomethyl)-6,6-difluorospiro[3.3]heptane-2-carboxylate hydrochloride (35):

Compound 34 (50.0 g, 0.16 mol) was dissolved in 2 M ethanolic HCl (400 mL) and the resulting solution was stirred at rt overnight. Then it was evaporated to dryness at reduced pressure, the residue was triturated with Et₂O (200 mL), and filtered to give the title compound 35 as white powder. Yield 38.5 g, 88%; m.p. 111–131 °C; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.19 (s, 3H), 4.13 (q, J = 7.1 Hz, 2H), 3.33 (s, 2H), 2.67 (dt, J = 18.7, 12.7 Hz, 4H), 2.47 (d, J = 12.7 Hz, 2H), 2.37 (d, J = 12.7 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H) ppm; ¹³C{¹H} NMR (151 MHz, DMSO-d₆): δ = 173.9, 120.5 (t, J = 278.6 Hz), 61.5, 47.8 (t, J = 21.4 Hz), 47.4 (t, J = 21.5 Hz), 43.6, 41.3, 39.4, 26.7 (t, J = 9.6 Hz), 14.3 ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ = −89.6 ppm; MS (APCI): m/z = 234 [M+H]⁺; elemental analysis calcd. (%) for C₁₁H₁₈ClF₂NO₂: C 48.98, H 6.73, N 5.19; found: C 49.05, H 6.33, N 5.44.

(2-(Aminomethyl)-6,6-difluorospiro[3.3]heptan-2-yl)methanol hydrochloride (36):

Compound 8 (40.0 g, 0.17 mol) was added portionwise to the stirred suspension of LiAlH₄ (13.3 g, 0.35mol) in THF (500 mL) at rt and the resulting mixture was refluxed with stirring for 1 h. Then it was cooled to 0 °C and quenched by sequential dropwise addition of water (13 mL), 50% aq. NaOH (8.7 mL), and water (40 mL) while maintaining the above temperature. The precipitate was filtered off and the filtrate was evaporated at reduced pressure. The residue was dissolved in Et₂O (300 mL) followed by addition of 4M HCl in Et₂O (40mL) and the resulting mixture was evaporated to dryness at reduced pressure. The residue was recrystallized from EtOAc – hexanes (1:5) to give the title compound 36 as yellowish crystals. Yield 27.8 g, 70%; m.p. 135–137 °C; ¹H NMR (400 MHz, DMSO-d₆): δ = 7.92 (s, 3H), 5.10 (s, 1H), 3.41 (s, 2H), 2.85 (s, 2H), 2.60 (td, J = 12.6, 7.0 Hz, 4H), 2.07 (d, J = 12.6 Hz, 2H), 1.96 (d, J = 12.6 Hz, 2H) ppm; ¹³C{¹H} NMR (126 MHz, DMSO-d₆): δ = 120.7 (t, J = 279.2 Hz), 65.4, 48.2 (t, J = 21.0 Hz), 47.8 (t, J = 21.0 Hz), 44.5, 38. 6, 37.3, 26.1 (t, J = 9.0 Hz) ppm; ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆): δ = −89.3 ppm; MS (APCI): m/z = 192 [M+H]⁺; elemental analysis calcd. (%) for C₉H₁₆ClF₂NO: C 47.48, H 7.08, N 6.15; found: C 47.58, H 6.93, N 6.15.

Scheme 5.

The synthesis of amine 15.