Synthesis of 4‐(R)‐Naphthalene‐2‐yloxy‐1‐(1‐Phenyl‐(S)‐Ethyl)‐Pyrrolidin‐3‐(R)‐ol and 4‐(S)‐Naphthalen‐2‐yloxy‐1‐(1‐Phenyl‐(S)‐Ethyl)‐Pyrrolidin‐3‐(S)‐ol: Versatile Chiral Intermediates for Synthesis

Abstract

A convenient and rapid synthesis of 4‐(R)‐(naphthalen‐2‐yloxy)‐1‐(1‐phenyl‐(S)‐ethyl)‐pyrrolidin‐3‐(R)‐ol and 4‐(S)‐(naphthalen‐2‐yloxy)‐1‐(1‐phenyl‐(S)‐ethyl)‐pyrrolidin‐3‐(S)‐ol is disclosed. The reaction scheme is highlighted by the meso‐epoxidation of 1‐(1‐phenyl‐(S)‐ethyl)‐2,5‐dihydro‐1H‐pyrrole followed by addition of 2‐naphthol alkoxide to provide both expected diastereoisomers. Separation of the diastereoisomers by crystallization provided access to both diastereoisomers in modest yield without the employment of expensive chiral catalysts. X‐ray analysis of one of the diastereoisomers led to the unambiguous assignment of each diastereoisomer. These chiral pyrrolidine analogues should be useful as intermediates in natural product, combinatorial/parallel synthesis, and medicinal chemistry.

Keywords:

• Chiral 3,4‐disubstituted pyrrolidines
• Meso‐epoxide ring opening
• Pyrrolidine analogs

Notes

^aCompound B was characterized by ¹H NMR, COSY, HSQC, and NOESY (data not shown).

bCrystallographic Experimental Details:A. Crystal Data	=
Formula	=	C22H23NO2
Formula weight	=	333.41
Crystal dimensions (mm)	=	0.46 × 0.36 × 0.23
Crystal system	=	Monoclinic
Space group	=	I2 (an alternate setting of C2 [No. 5])
Unit cell parameters1	=
a(Å)	=	18.3026 (18)
b(Å)	=	6.8814 (7)
c(Å)	=	14.7614 (15)
β(deg)	=	103.926 (2)
V(Å3)	=	1804.5 (3)
Z	=	4
ρ calcd. (g cm−3)	=	1.227
μ (mm−1)	=	0.078
B. Data Collection and Refinement Conditions	=
Diffractometer	=	Bruker PLATFORM/SMART 1000 CCD2
Radiation (λ[Å])	=	Graphite‐monochromated Mo Kα (0.71073)
Temperature (°C)	=	−80
Scan type	=	ω scans (0.2°) (25 s exposures)
Data collection 2θ limit (deg)	=	52.76
Total data collected	=	4609 (−20 ≤ h ≤ 22, −8 ≤ k ≤ 8, −12 ≤ l ≤ 18)
Independent reflections	=	3481 (R int = 0.0241)
Number of observed reflections (NO)	=	3140 [F o 2 ≥ 2σ (F o 2)]
Structure solution method	=	Direct methods (SHELXS‐86 3a)
Refinement method	=	Full‐matrix least‐squares on F 2 (SHELXL‐93 3b 3)
Absorption correction method	=	Multi‐scan (SADABS)
Range of transmission factors	=	0.9823–0.9650
Data/restraints/parameters	=	3481 [F o 2 ≥ −3σ(F o 2)]/0/227
Flack absolute structure parameter[3c], 4	=	0.3 (11)
Goodness‐of‐fit (S)5	=	1.038 [F o 2 ≥ −3σ(F o 2)]
Final R indices6	=
R1 [F o 2 ≥ 2σ(F o 2)]	=	0.0356
wR 2[F o 2 ≥ −3σ(F o 2)]	=	0.0878
Largest difference peak and hole	=	0.189 and −0.123 e Å−3

¹Obtained from least‐squares refinement of 3039 reflections with 5.69° < 2θ < 52.52°.

²Programs for diffractometer operation, data collection, data reduction, and absorption correction were those supplied by Bruker.

³Refinement on F _o ² for all reflections [all of these having F _o ² ≥ −3σ(F _o ²)]. Weighted R‐factors wR ₂ and all goodnesses of fit S are based on F _o ²; conventional R‐factors R ₁ are based on F _o, with F _o set to zero for negative F _o ². The observed criterion of F _o ² > 2σ(F _o ²) is used only for calculating R ₁, and is not relevant to the choice of reflections for refinement. R‐factors based on F _o ² are statistically about twice as large as those based on F _o, and R‐factors based on all data will be even larger.

⁴The Flack parameter will refine to a value near zero if the structure is in the correct configuration and will refine to a value near one for the inverted configuration. In this case, the absolute structure cannot be reliably determined from the x‐ray data, but can be assigned based upon the known stereochemistry of the precursor pyrrolidin‐3,4‐diol.

⁵ S = [Σw(F _o ² − F _c ²)²/(n − p)]^1/2 (n = number of data; p = number of parameters varied; w = [σ²(F _o ²) + (0.0387P)² + 0.4245P]⁻¹, where P = [Max(F _o ², 0) + 2F _c ²]/3).

⁶ R ₁ = Σ‖F _o| − |F _c‖/Σ|F _o|; wR ₂ = [Σw(F _o ² − F _c ²)²/Σw(F _o ⁴)]^1/2.