(Z,1S,10aR)-(−)-Menthyl 1-hy­droxy-1,2,3,5,6,7,10,10a-octa­hydro­pyrrolo­[1,2-a]azocine-10a-carboxyl­ate

Daniele Muroni; Emilio Napolitano; Olivier Perez; Nicola Culeddu; Antonio Saba

doi:10.1107/S1600536812027900

. 2012 Jun 27;68(Pt 7):o2224–o2225. doi: 10.1107/S1600536812027900

(Z,1S,10aR)-(−)-Menthyl 1-hydroxy-1,2,3,5,6,7,10,10a-octahydropyrrolo[1,2-a]azocine-10a-carboxylate

Daniele Muroni ^a,^*, Emilio Napolitano ^a, Olivier Perez ^b, Nicola Culeddu ^c, Antonio Saba ^a

PMCID: PMC3394017 PMID: 22798882

Abstract

The structure determination confirms the stereochemistry of the title compound, C₂₁H₃₅NO₃, obtained as an intermediate in the enantioselective synthesis of deoxynojirimicine analogs. The system contains a pyrrolo[1,2-a]azocine backbone, which was synthesized by a domino process involving a [2,3]-sigmatropic rearrangement. The incorporation of a chiral auxiliary (−)-menthyl, whose stereocentres are not involved during the synthesis, enables the assignation of absolute configuration. The crystal structure features O—H⋯O hydrogen bonds involving the hydroxy groups as donors and the carbonyl groups as acceptors, which link the molecules into chains running along [010].

Related literature

For the construction of the pyrrolo[1,2-a]azocine backbone by the domino sequence, see: Clark et al. (2001 ▶); Muroni et al. (2006 ▶). For domino processes promoted by catalytic decomposition of diazocompounds, see: Doyle et al. (1997 ▶). For [2,3]-sigmatropic rearrangement, see: Sweeney (2009 ▶); Zhang & Wang (2010 ▶). For manzamine alkaloids and other biologically active compounds containing the pyrrolo[1,2-a]azocine subunit, see: Rao et al. (2006 ▶); Yap et al. (2011 ▶); Sun et al. (2011 ▶). For deoxynojirimicine and iminosugars, see: Asano et al. (2000 ▶); Watson et al. (2001 ▶). For chiral auxiliary (−)-menthyl, see: Wang et al. (2006 ▶).

Experimental

Crystal data

C₂₁H₃₅NO₃
M _r = 349.5
Orthorhombic,
a = 10.7804 (8) Å
b = 7.7938 (7) Å
c = 23.8862 (17) Å
V = 2006.9 (3) Å³
Z = 4
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 120 K
0.36 × 0.13 × 0.13 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2008 ▶) T _min = 0.716, T _max = 0.746
21709 measured reflections
3281 independent reflections
2331 reflections with I > 3σ(I)
R _int = 0.048

Refinement

R[F ² > 2σ(F ²)] = 0.041
wR(F ²) = 0.047
S = 1.23
3281 reflections
230 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.23 e Å⁻³
Δρ_min = −0.28 e Å⁻³

Data collection: APEX2 (Bruker, 2005 ▶); cell refinement: SAINT (Bruker, 2007 ▶); data reduction: SAINT; program(s) used to solve structure: SIR2011 (Burla et al., 2012 ▶); program(s) used to refine structure: JANA2006 (Petricek et al., 2006 ▶); molecular graphics: DIAMOND (Brandenburg & Putz, 2005 ▶) and ORTEP-3 (Farrugia, 1997 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶) and PLATON (Spek, 2009 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812027900/bh2433sup1.cif

e-68-o2224-sup1.cif^{(20.4KB, cif)}

Supplementary material file. DOI: 10.1107/S1600536812027900/bh2433Isup2.cdx

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812027900/bh2433Isup3.hkl

e-68-o2224-Isup3.hkl^{(157.3KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812027900/bh2433Isup4.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1o⋯O2ⁱ	0.81 (2)	2.02 (2)	2.8259 (19)	174 (2)

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Symmetry code: (i) Inline graphic .

Acknowledgments

The authors are thankful to the Fondazione Banco di Sardegna and the Regione Autonoma della Sardegna (programma operativo FSE Sardegna 2007–2013 legge regionale 7 agosto 2007, n. 7 promozione della ricerca scientifica e dell’innovazione tecnologica in Sardegna). EN is particularly grateful to Professor D. Chateigner and the staff of the CRISMAT Laboratoire (Caen, France) for crystallographic support and useful discussions about diffraction.

supplementary crystallographic information

Comment

The pyrrolo[1,2-a]azocine backbone is contained as the CE subunit in the structures of manzamine and ircinal alkaloids (Rao et al., 2006), as well as other natural and synthetic compounds which have shown interesting biological properties (Yap et al., 2011; Sun et al., 2011). Among the methods for a rapid construction of bicycle alkaloid, domino processes promoted by catalytic decomposition of diazo compounds have become commonly employed since they give a rapid access to complex structures in a stereoselective way (Doyle et al., 1997; Clark et al., 2001).

The used route for the synthesis of the title compound is described in Figure 1. The diazocarbonyl derivative 1 was synthesized starting from L-proline and (–)-menthyl acetate. The decomposition in refluxing toluene with Cu(acac)₂ or Rh₂(OAc)₄ brought in one step to the pyrroloazocine alkaloid 3. The decomposition triggers a domino process that involved a carbenoidic attack to the nitrogen lone pair and the formation of the [5,5]-spirocyclic ammonium ylide 2. The ylide undergoes a [2,3]-sigmatropic rearrangement and it was possible to isolate the alkaloid 3 in 70% yield and 97% enantiomeric excess (Muroni et al., 2006). The stereo specific nature of [2,3]-sigmatropic rearrangement allows a complete transfer of chirality (Sweeney, 2009; Zhang & Wang, 2010). As first step in the conversion in deoxynojirimicine analogs (Asano et al., 2000; Watson et al., 2001), the reduction of the carbonyl with L-selectride gave, after chromatography and recrystallization, the title compound 4 as a single diastereoisomer. The structure determination confirms the configuration of the quaternary stereocentre formed during the domino sequence and the configuration of the carbinol function, which is in accordance with the attack of L-selectride at the opposite face of the ester function.

The structural model (Fig. 2) showed standard bond lengths and angles; the X-ray analysis confirmed a cis C7═C8 double bond in the azocine ring, and the stereochemistry of C atoms known from literature in the auxiliary chiral (–)-menthyl: S-C13, R-C12 and R-C16. Two new chiral centers were identified S-C1 and R-C10.

The crystal structure (Fig. 3 and 4) consists of one type of O—H···O hydrogen-bond, with each molecule acting as a donor and acceptor of two hydrogen bonds. One molecule is linked through hydrogen interaction to other two symmetry-related molecules in the crystal, resulting in the formation of chains parallel to the [010] direction.

Experimental

All ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on a Varian Mercury plus 400 spectrometer. Infrared (IR) spectra were performed on a FT/IR-480plus JASKO spectrophotometer. The optical rotations were measured by a polarimeter P-1010 JASCO in a 1 dm tube. All reagents and solvents employed were reagent grade materials purified by standard methods and redistilled before use. (1R)-(–)-menthyl acetate (>98%) and L-proline (>99.0%) were purchased from Sigma-Aldrich.

To a solution of compound 3 (210 mg, 0.6 mmol, see Fig. 1) in dry THF (5 ml) was added L-selectride (1.21 ml of 1.0 M solution in THF, 1.21 mmol) dropwise at 273 K. The reaction mixture was stirred for 1 h at 273 K and then allowed to warm to room temperature for another 1 h. The mixture was then diluted with EtOAc (50 ml) and filtered through a pad of silica gel, which was rinsed with EtOAc (50 ml). The filtrate was concentrated under reduced pressure, and the residue purified by flash chromatography (petroleum ether/ethyl acetate, 9:1) to give 180 mg of 4 (85%) as white oil. Recrystallization from EtOH/H₂O (8:2) gave the title compound 4 as white crystals: m.p. 389 K; [α]²⁵_D = -92.94 (c 0.32, CHCl₃); ¹H NMR (CDCl₃): δ 0.74 (d, 3H, J=7.0 Hz), 0.89 (d, 3H, J=6.8 Hz), 0.91 (d, 3H, J=6.8 Hz), 0.80–1.11 (m, 3H), 1.30–1.58 (m, 3H), 1.60–1.73 (m, 3H), 1.73–1.86 (m, 1H), 1.92–2.10 (m, 3H), 2.12–2.32 (m, 3H), 2.37 (d, 1H, J=8.4 Hz), 2.64–2.80 (m, 2H), 2.92 (ddd, 1H, J=15.8, 12.1, 3.1 Hz), 3.00 (dt, 1H, J=9, 5.2 Hz), 3.15 (dt, 1H, J=8.4, 5.2 Hz), 3.98 (q, 1H, J=8.0 Hz), 4.74 (dt, 1H, J=4.4, 10.8 Hz), 5.65–5.80 p.p.m. (m, 2H). ¹³C NMR (CDCl₃): δ 15.71, 20.90, 22.03, 22.91, 25.40, 25.89, 29.12, 31.39, 31.45, 32.50, 34.22, 41.18, 47.07 48.21, 50.04, 74.97, 75.08, 78.01, 126.17, 132.84, 173.64 p.p.m.; IR (neat): 3465, 3019, 2954, 1708, 1456, 1214 cm^-1. Anal. Calc. for C₂₁H₃₅NO₃: C 72.17, H 10.09, N 4.01%; Found: C 72.20, H 10.05, N 4.05%.