Titanium-Mediated Cyclopropanation on Diesters: Mechanistic Study on the Dramatic Effects of Selected Parameters

Abstract

Competitive reactions of diisopropyloxy(η^²-alkene)titanium on N-allyl diesters derived from natural amino acids and performed under varying conditions (temperature, nature, and concentration of Grignard reagents) show different regio- and chemoselectivities. In light of the isolated reaction products, a possible mechanism of the formation of original products is discussed.

Recently, [¹] we have studied the regio- and stereoselectivity of the Kulinkovich reaction [²] performed on aspartic acid derivative 1, and we observed, under classical experimental conditions [Ti(Oi-Pr)₄, C₆H₁₁MgCl], the formation of only the unexpected pyrrolidinone 2. On the other hand, Joullié et al. [³] obtained the expected azabicyclo[3.1.0]hexan-1-ol 3 when performing the same reaction, but with ClTi(Oi-Pr)₃ as catalyst (Scheme  [¹] ).

It is noteworthy that the same reaction, performed on the homologous glutamic acid derivative 4, only afforded the corresponding azabicyclo[3.1.0]hexan-1-ol 5 even in the presence of the titanium tetraisopropoxide (Scheme  [²] ). [4]

In the present work, we observed that, under classical cyclopropanation conditions [1 equiv of Ti(Oi-Pr)₄, 4-5 equiv of C₆H₁₁MgCl (2-2.4 M in Et₂O), Et₂O-THF (1:1), 4 h, 20 ˚C], the N-allyl dimethyl aspartate derivative 1a afforded an inseparable mixture of pyrrolidinones 2a,b and a small amount of trans-esterified aspartate derivative 1b. Moreover, from the diesters 1a or 1b, no product resulting from a possible reaction between the excess of Grignard and the ester or ketone functions of the newly formed pyrrolidinones 2a or 2b was observed (Scheme  [³] ).

To avoid trans-esterification, all the reactions were thus performed on isopropyl esters 1b. The reactions were carried out in presence of titanium catalyst by dropwise addition of four equivalents of cyclohexyl Grignard reagent at a given temperature over three hours. Then, after an additional hour at the same temperature, the reaction was quenched and the products isolated. NMR analysis of the crude product allowed the determination of the cis/trans ratios, while yields were calculated after purification by column chromatography.

Table 1 Effects of the Amount of Ti(Oi-Pr)₄ and the Temperature on the Formation of Pyrrolidinone 2b

Entry	Ti(Oi-Pr)4˙(n)	Temp (˚C)	Yield (%)	Ratio (cis/trans)
1	1	-78	18	27:73
2	1	-40	25	27:73
3	1	0	34	24:76
4	1	20	53	20:80
5	1	50	45	18:82
6	0.1	20	20	22:78
7	2	20	35	23:77

Parameters such as temperature and amount of titanium isopropylate, which are able to affect the sequence of the reaction, were tested (Table  [¹] ).

Firstly, we noted that the use of either 5 or 6 equivalents of the Grignard reagent had no significant influence on the yield or cis/trans product ratio of the reaction. Unsatisfactory yields were observed for the reactions carried out at low temperatures (entries 1-3) while the best result was obtained performing the reaction at room temperature (entry 4). At a higher temperature of 50 ˚C (entry 5) the yield was lower, but the selectivity was essentially maintained. However, reducing (entry 6) or increasing (entry 7) the amounts of the titanium species led to lower yields although the variations of the cis/trans ratios remained almost unchanged.

On the other hand, isopropyl magnesium bromide or ­chloride had been initially used by Sato [5] as a source of Grignard reagent in certain intramolecular cyclopropanation reactions; surprisingly, when applied to the aspartate derivative 1b, the formation of the pyrrolidinone 6 was observed, and in yields highly dependent upon the concentration of the organometallic reagent (Table  [²] ).

Table 2 Effects of the Concentration of Grignard Reagent on the Synthesis of Pyrrolidinones 2b and 6

Entry	i-PrMgBr (mol˙L-¹)	Temp (˚C)	Yield of 2b (%), ­ratio (cis/trans)	Yield of 6 (%), ratio (cis/trans)
1	0.5	20	49 (19:81)	0
2	1.2	20	28 (22:78)	16 (21:79)
3	1.8	20	15 (24:76)	29 (26:74)
4	2.4	20	0	51 (28:72)
5	2.4	0	0	27 (25:75)
6	2.4	-40	0	23 (27:73)
7	2.4	-78	0	13 (23:77)

Indeed, in the presence of five equivalents of isopropyl magnesium bromide at a concentration of approximately 0.5 mol L^-¹ (entry 1), the aspartate derivative only furnished pyrrolidinones 2b with a yield close to that previously obtained with cyclohexyl magnesium chloride and similar diastereomeric ratio. However, at concentrations above 1 mol L^-¹ at room temperature, a dramatic effect was observed, and the formation of ketone 6 became preponderant to exclusive, according to the increasing concentration (entries 2-4). On the other hand, lowering the temperature only affected the yield of the product negatively (entry 5-7).

Although high concentrations promote intermolecular reactions, no report of such selectivity in the Kulinkovich reaction has appeared in the literature. [6] As depicted in Scheme  [4] , the formation of the ketone 6 can occur through the incorporation of titanium complex 7 in the ester function of the pyrrolidinone 2b giving the oxatitanacyclopentane 8, then the cyclopropanol 9 which, on ring opening, leads to the ketopyrrolidinone 6 [7] (Scheme  [4] ).

Compared to the bulky cyclopentyl- or cyclohexylmagnesium halide, the incorporation of the titanium complex 7 seems quite conceivable. The hypothesis of a possible coordination between the titanium species and the oxygen of the ketone function could stabilize the complex form 8′ sufficiently, such that simple hydrolysis would lead directly to the ketopyrrolidinone 6. On the other hand, the ring opening on the side chain could be possible but perhaps less likely.

This result can be extended to the formation of the monocyclic pyrrolidinone skeleton of ester 2b (vide supra Scheme  [¹] ). Indeed, as represented in Scheme  [5] , following formation of titanium species 10, the coordination of the weak Lewis acid (XMgOi-Pr) from Ti(Oi-Pr)₄ between the ester on the side chain and the Oi-Pr residue of the ­oxatitanacyclopentane 11a (path a) does not constitute a sufficient driving force to achieve the contraction cycle, thus a subsequent hydrolysis leads to the pyrrolidinone 2b. In support of this theory, performing the reaction in the presence of trimethylsilyl chloride gives a similar result. On the other hand, the reaction carried out with ClTi(Oi-Pr)₃ (path b) releases a stronger Lewis acid (XMgCl) which, on coordination to give the complex 11b, is capable of inducing formation of the titanium salt 12. In this case, simple hydrolysis yields the stable azabicyclo[3.1.0]hexanol 3b isolated by Joullié.

Further evidence supporting our previous assumption came to light when extending this experiment to the glutamate derivative 4 which, as we had reported before, does not undergo cyclopropyl ring opening under titanium isopropoxide mediated conditions (vide supra Scheme  [²] ).

Indeed, extending the ester on the side chain does not allow the previous coordination and, as expected, a cis/trans inseparable mixture of azabicyclo[3.1.0]hexanols 13 and 14 resulting from a double Kulinkovich reaction occurred in the presence of a high concentration of Grignard reagent (Table  [³] ).

Table 3 Effects of the Concentration of Grignard Reagent on the Synthesis of Cyclopropanols 5, 13, and 14 [7]

Entry	i-PrMgBr (X mol˙L-¹)	Yield of 5 (%), ratio (cis/trans)	Yield of 13 (%), ratio (cis/trans)	Yield of 14 (%), ratio (cis/trans)
1	0.5	50 (69:31)	0	0
2	2.4	0	26 (60:40)	17 (64:36)

In conclusion, we have investigated alternative experimental conditions allowing different cyclopropanol derivatives to be obtained. The influence of several parameters such as temperature, titanium catalyst, nature, and concentration of Grignard reagent were studied in order to ­optimize reactions which may even be competitive. Meanwhile, novel mechanisms have been proposed to explain the formation of primary or secondary unexpected products.

Acknowledgment

The authors gratefully acknowledge Professor Oleg Kulinkovich, Belarusian State University of Minsk, for helpful discussions.

References and Notes

• 1 Garnier J.-M. Jida M. Ollivier J. Synlett  2006,  2739 
  Thieme Connect
• 2 Kulinkovich OG. Chem. Rev.  2003,  103:  2597 
  CrossrefPubMedSearch in Google Scholar
• 3 Faler CA. Joullié MM. Tetrahedron Lett.  2008,  49:  6512 
  CrossrefSearch in Google Scholar
• 4 Jida M. PhD Thesis   Université de Paris-Sud 11; France: 2008. 
• 5a Kasatkin A. Nakagawa T. Okamoto S. Sato F. J. Am. Chem. Soc.  1995,  117:  3881 
  Search in Google Scholar
• 5b Nakagawa T. Kasatkin A. Sato F. Tetrahedron Lett.  1995,  36:  3207 
  Search in Google Scholar
• 5c Harada K. Urabe H. Sato F. Tetrahedron Lett.  1995,  36:  3203 
  Search in Google Scholar
• 5d Urabe H. Hata T. Sato F. Tetrahedron Lett.  1995,  36:  4261 
  Search in Google Scholar
• 6 Kulinkovich OG. Kananovich DG. Eur. J. Org. Chem.  2007,  2121 

Selected Data
tert -Butyl 3-{3-Benzyl-1-hydroxy-3-azabicyclo-[3.1.0]hex-2-yl} Propanoate (5)
Colourless liquid. IR (neat): 3333, 3027, 2931, 1740, 1602 cm^-¹. ^¹H NMR (360 MHz, CDCl₃): δ = 7.34-7.24 (m, 10 H, cis + trans), 5.18-5.01 (m, 2 H, cis + trans), 4.09 (d, J = 13.7 Hz, 1 H, cis), 4.00 (d, J = 13.3 Hz, 1 H, trans), 3.86 (d, J = 13.7 Hz, 1 H, cis), 3.75 (d, J = 13.3 Hz, 1 H, trans), 3.23 (dd, J = 12.6, 6.1 Hz, 1 H, cis), 3.15 (dd, J = 9.7, 4.7 Hz, 1 H, trans), 2.80 (t, J = 4.5 Hz, 1 H, trans), 2.69 (t, J = 4.5 Hz, 1 H, cis), 2.55 (d, J = 12.6 Hz, 1 H, cis), 2.36 (d, J = 9.7 Hz, 1 H, trans), 2.06-1.90 (m, 4 H, cis + trans), 1.87-1.73 (m, 4 H, cis + trans), 1.60-1.54 (m, 2 H, cis + trans), 1.28-1.23 (m, 2 H, cis + trans), 1.25 (d, J = 6.2 Hz, 3 H, trans), 1.22 (d, J = 6.9 Hz, 3 H, cis), 1.20 (d, J = 6.9 Hz, 3 H, cis), 1.18 (t, J = 4.8 Hz, 1 H, trans), 1.15 (d, J = 6.2 Hz, 3 H, trans), 1.11 (dd, J = 9.0, 5.8 Hz, 1 H, cis), 0.87 (dd, J = 10.1, 4.8 Hz, 1 H, trans), 0.46 (t, J = 5.8 Hz, 1 H, cis). ^¹³C NMR (63 MHz, CDCl₃): δ = 170.8 (cis), 170.6 (trans), 137.9 (cis), 137.8 (trans), 128.9 (cis), 128.7 (trans), 128.5 (cis), 128.3 (trans), 127.3 (cis), 127.2 (trans), 68.4 (cis), 68.2 (trans), 66.6 (cis), 65.8(trans), 59.4 (cis), 59.1 (trans), 58.3 (cis), 58.1 (trans), 55.7 (trans), 54.9 (cis), 36.8 (cis), 35.9 (trans), 25.8 (cis), 24.5 (trans), 21.7 (cis), 21.1 (trans), 20.9 (cis), 20.2 (trans), 15.8 (cis), 15.6 (trans). MS (EI, trans isomer): m/z (%) = 303(9) [M⁺], 160 (48), 96 (27), 91 (100). MS (EI, cis isomer): m/z (%) = 303(6) [M⁺], 234 (45), 188 (42), 91 (100). HRMS (ES): m/z calcd for C₁₈H₂₆NO₃ [M + H]⁺: 304.19070; found: 304.19057.
1-Benzyl-4-methyl-2-(2-oxopentyl)-3-pyrrolidinone (6)
Colourless liquid. IR (neat): 3057, 3027, 2955, 1758, 1603 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 7.36-7.27 (m, 10 H, cis + trans), 3.88 (d, J = 13.0 Hz, 1 H, cis), 3.85 (d, J = 13.0 Hz, 1 H, trans), 3.48 (d, J = 13.7 Hz, 1 H, cis), 3.46 (d, J = 13.0 Hz, 1 H, trans), 3.40 (t, J = 8.3 Hz, 1 H, trans), 3.29 (t, J = 5.0 Hz, 1 H, cis), 3.01 (dd, J = 11.2, 9.0 Hz, 1 H, trans), 2.85 (dd, J = 12.6, 7.2 Hz, 1 H, cis), 2.73 (dd, J = 12.6, 7.2 Hz, 1 H, cis), 2.68 (dd, J = 11.2, 8.3 Hz, 2 H, cis), 2.67-2.60 (m, 2 H, cis + trans), 2.63 (dd, J = 10.0, 5.0 Hz, 2 H, trans), 2.27-2.20 (m, 4 H, cis + trans), 2.08 (dd, J = 11.2, 9.0 Hz, 1 H, trans), 1.60-1.54 (m, 4 H, cis + trans), 1.21 (d, J = 7.6 Hz, 3 H, cis), 1.14 (d, J = 7.2 Hz, 3 H, trans), 1.07 (t, J = 7.6 Hz, 3 H, cis), 1.06 (t, J = 7.6 Hz, 3 H, trans). ^¹³C NMR (63 MHz, CDCl₃): δ = 217.7 (cis), 217.5 (trans), 208.1 (cis), 207.8 (trans), 138.2 (cis), 138.0 (trans), 128.9 (trans), 128.7 (cis), 128.4 (cis), 128.2 (trans), 127.5 (trans), 127.3 (cis), 66.4 (trans), 66.0 (cis), 59.4 (trans), 58.9 (cis), 57.9 (trans), 56.7 (cis), 45.2 (cis), 43.1 (trans), 41.9 (cis + trans), 36.2 (cis), 35.3 (trans), 18.0 (cis), 17.1 (cis), 17.0 (trans), 16.0 (cis), 13.7 (trans), 11.9 (trans). MS (EI, trans isomer): m/z (%) = 273 (5) [M⁺], 86 (40), 84 (61), 55 (55), 51 (35), 49 (100), 44 (49), 40 (90). MS (EI, cis isomer):
m/z (%) = 273 (4) [M⁺], 91 (100), 86 (41). HRMS (ES): m/z calcd for C₁₇H₂₄NO₂ [M + H]⁺: 274.18020; found: 274.18082.
(1 S ,2 S )-3-Benzyl-2-[2-(1-hydroxy-2-methylcyclopropyl)-ethyl]-3-azabicyclo[3.1.0]hexan-1-ol (13)
[Insepable mixture of undetermined cis and trans diastereomers (ratio 60:40: major a and minor b) on the side chain.] Colorless liquid. IR (neat): 3030, 2929, 2797, 1603 cm^-¹. ^¹H NMR (360 MHz, CDCl₃): δ = 7.34-7.26 (m, 10 H, a + b), 4.14 (d, J = 14.4 Hz, 1 H, b), 4.08 (d, J = 14.4 Hz, 1 H, b), 3.76 (d, J = 13.7 Hz, 1 H, a), 3.71 (d, J = 13.7 Hz, 1 H, a), 3.23 (dd, J = 12.6, 5.8 Hz, 1 H, b), 3.06 (dd, J = 9.7, 4.3 Hz, 1 H, a), 2.92 (t, J = 4.7 Hz, 1 H, a), 2.65 (t, J = 4.2 Hz, 1 H, b), 2.53 (d, J = 12.6 Hz, 1 H, b), 2.44 (d, J = 9.7 Hz, 1 H, a), 2.21-2.17 (m, 4 H, a + b), 2.06-1.97 (m, 4 H, a + b), 1.63-1.54 (m, 2 H, a + b), 1.44-1.39 (m, 2 H, a + b), 1.40 (t, J = 5.1 Hz, 1 H, a), 1.30-1.24 (m, 2 H, a + b), 1.26 (t, J = 5.8 Hz, 1 H, b), 1.18-1.08 (m, 2 H, a + b), 1.16 (d, J = 6.2 Hz, 3 H, a), 1.07 (d, J = 6.2 Hz, 3 H, b), 0.97-0.87 (m, 4 H, a + b), 0.81 (dd, J = 9.4, 5.1 Hz, 1 H, a), 0.07 (dd, J = 10.2, 5.8 Hz, 1 H, b). ^¹³C NMR (63 MHz, CDCl₃): δ = 139.7 (b), 137.9 (a), 129.6 (b), 128,7 (a), 128.5 (b), 128.3 (a), 128.2 (b), 127.5 (a), 70.2 (b), 70.1 (a), 65.7 (a), 64.6 (b), 57.8 (b), 57.7 (a), 55.8 (a), 55.7 (b), 54.1 (a), 53.4 (b), 37.3 (a), 31.1 (b), 24.6 (a), 24.5 (b), 22.7 (a), 22.1 (b), 20.2 (a), 18.4 (b), 17.4 (a), 16.5 (b), 14.4 (a), 13.8 (b), 12.4 (b), 11.4 (a). MS (EI, isomer a): m/z (%) = 287 (5)[M⁺], 218 (18), 200(20), 188(47), 91(100). MS (EI, isomer b): m/z (%) = 287 (6) [M⁺], 218 (17), 200(26), 188 (29), 91(100). HRMS (ES): m/z calcd for C₁₈H₂₆NO₂ [M + H]⁺: 288.19580; found: 288.19622.
(1 R ,2 S ) - 3-Benzyl-2-[2-(1-hydroxy-2-methylcyclo-propyl)ethyl]-3-azabicyclo[3.1.0]hexan-1-ol (14) [Inseparable mixture of undetermined cis and trans diastereomers (ratio 64:36: major a and minor b) on the
side chain.] Colourless liquid. IR (neat): 3036, 2929, 2791, 1602 cm^-¹. ^¹H NMR (360 MHz, CDCl₃): δ = 7.34-7.25 (m, 10 H, a + b), 3.84 (d, J = 13.3 Hz, 1 H, a), 3.83 (d, J = 13.3 Hz, 1 H, b), 3.64 (d, J = 13.3 Hz, 1 H, a), 3.63 (d, J = 13.3 Hz, 1 H, b), 3.17 (dd, J = 10.1, 4.7 Hz, 1 H, b), 3.02 (t, J = 4.2 Hz, 1 H, a), 2.97 (t, J = 4.2 Hz, 1 H, b), 2.34 (d, J = 9.4 Hz, 1 H, a), 2.31 (d, J = 10.1 Hz, 1 H, b), 2.29 (dd, J = 9.4, 4.0 Hz, 1 H, a), 2.01-1.92 (m, 4 H, a + b), 1.83-1.73 (m, 4 H, a + b), 1.59-1.54 (m, 2 H, a + b), 1.47-1.45 (m, 2 H, a + b), 1.29 (t, J = 6.7 Hz, 1 H, a), 1.28-1.25 (m, 2 H, a + b), 1.17 (dd, J = 9.0, 5.4 Hz, 1 H, b), 1.06 (d, J = 6.7 Hz, 3 H, a), 1.04 (d, J = 6.7 Hz, 3 H, b), 0.93 (dd, J = 9.0, 6.7 Hz, 1 H, a), 0.86-0.81 (m, 2 H, a + b), 0.76-0.73 (m, 4 H, a + b), 0.02 (t, J = 10.2 Hz, 1 H, b). ^¹³C NMR (63 MHz, CDCl₃): δ = 139.2 (b), 137.6 (a), 129.4 (a + b), 128,7 (b), 128.6 (a), 128.3 (b), 127.1 (a), 67.1 (b), 66.3 (a), 63.4 (a), 63.2 (b), 58.7 (a), 58.4 (b), 57.8 (a), 57.4 (b), 54.7 (b), 54.2 (a), 30.8 (a), 30.4 (b), 24.6 (a), 24.4 (b), 21.6 (a), 20.4 (b), 20.2 (a), 20.0 (b), 19.6 (a), 19.1 (b), 15.0 (a), 14.9 (b), 14.6 (b), 14.3 (a). MS (EI, isomer a): m/z (%) = 287 (9)[M⁺], 218 (21), 200 (23), 188 (22), 91 (100). MS (EI, isomer b): m/z (%) = 287(6) [M⁺], 218 (28), 200 (19), 188 (33), 91 (100). HRMS (ES): m/z calcd for C₁₈H₂₆NO₂ [M + H]⁺: 288.19580; found: 288.19653.

References and Notes

• 1 Garnier J.-M. Jida M. Ollivier J. Synlett  2006,  2739 
  Thieme Connect
• 2 Kulinkovich OG. Chem. Rev.  2003,  103:  2597 
  CrossrefPubMedSearch in Google Scholar
• 3 Faler CA. Joullié MM. Tetrahedron Lett.  2008,  49:  6512 
  CrossrefSearch in Google Scholar
• 4 Jida M. PhD Thesis   Université de Paris-Sud 11; France: 2008. 
• 5a Kasatkin A. Nakagawa T. Okamoto S. Sato F. J. Am. Chem. Soc.  1995,  117:  3881 
  Search in Google Scholar
• 5b Nakagawa T. Kasatkin A. Sato F. Tetrahedron Lett.  1995,  36:  3207 
  Search in Google Scholar
• 5c Harada K. Urabe H. Sato F. Tetrahedron Lett.  1995,  36:  3203 
  Search in Google Scholar
• 5d Urabe H. Hata T. Sato F. Tetrahedron Lett.  1995,  36:  4261 
  Search in Google Scholar
• 6 Kulinkovich OG. Kananovich DG. Eur. J. Org. Chem.  2007,  2121 

Selected Data
tert -Butyl 3-{3-Benzyl-1-hydroxy-3-azabicyclo-[3.1.0]hex-2-yl} Propanoate (5)
Colourless liquid. IR (neat): 3333, 3027, 2931, 1740, 1602 cm^-¹. ^¹H NMR (360 MHz, CDCl₃): δ = 7.34-7.24 (m, 10 H, cis + trans), 5.18-5.01 (m, 2 H, cis + trans), 4.09 (d, J = 13.7 Hz, 1 H, cis), 4.00 (d, J = 13.3 Hz, 1 H, trans), 3.86 (d, J = 13.7 Hz, 1 H, cis), 3.75 (d, J = 13.3 Hz, 1 H, trans), 3.23 (dd, J = 12.6, 6.1 Hz, 1 H, cis), 3.15 (dd, J = 9.7, 4.7 Hz, 1 H, trans), 2.80 (t, J = 4.5 Hz, 1 H, trans), 2.69 (t, J = 4.5 Hz, 1 H, cis), 2.55 (d, J = 12.6 Hz, 1 H, cis), 2.36 (d, J = 9.7 Hz, 1 H, trans), 2.06-1.90 (m, 4 H, cis + trans), 1.87-1.73 (m, 4 H, cis + trans), 1.60-1.54 (m, 2 H, cis + trans), 1.28-1.23 (m, 2 H, cis + trans), 1.25 (d, J = 6.2 Hz, 3 H, trans), 1.22 (d, J = 6.9 Hz, 3 H, cis), 1.20 (d, J = 6.9 Hz, 3 H, cis), 1.18 (t, J = 4.8 Hz, 1 H, trans), 1.15 (d, J = 6.2 Hz, 3 H, trans), 1.11 (dd, J = 9.0, 5.8 Hz, 1 H, cis), 0.87 (dd, J = 10.1, 4.8 Hz, 1 H, trans), 0.46 (t, J = 5.8 Hz, 1 H, cis). ^¹³C NMR (63 MHz, CDCl₃): δ = 170.8 (cis), 170.6 (trans), 137.9 (cis), 137.8 (trans), 128.9 (cis), 128.7 (trans), 128.5 (cis), 128.3 (trans), 127.3 (cis), 127.2 (trans), 68.4 (cis), 68.2 (trans), 66.6 (cis), 65.8(trans), 59.4 (cis), 59.1 (trans), 58.3 (cis), 58.1 (trans), 55.7 (trans), 54.9 (cis), 36.8 (cis), 35.9 (trans), 25.8 (cis), 24.5 (trans), 21.7 (cis), 21.1 (trans), 20.9 (cis), 20.2 (trans), 15.8 (cis), 15.6 (trans). MS (EI, trans isomer): m/z (%) = 303(9) [M⁺], 160 (48), 96 (27), 91 (100). MS (EI, cis isomer): m/z (%) = 303(6) [M⁺], 234 (45), 188 (42), 91 (100). HRMS (ES): m/z calcd for C₁₈H₂₆NO₃ [M + H]⁺: 304.19070; found: 304.19057.
1-Benzyl-4-methyl-2-(2-oxopentyl)-3-pyrrolidinone (6)
Colourless liquid. IR (neat): 3057, 3027, 2955, 1758, 1603 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 7.36-7.27 (m, 10 H, cis + trans), 3.88 (d, J = 13.0 Hz, 1 H, cis), 3.85 (d, J = 13.0 Hz, 1 H, trans), 3.48 (d, J = 13.7 Hz, 1 H, cis), 3.46 (d, J = 13.0 Hz, 1 H, trans), 3.40 (t, J = 8.3 Hz, 1 H, trans), 3.29 (t, J = 5.0 Hz, 1 H, cis), 3.01 (dd, J = 11.2, 9.0 Hz, 1 H, trans), 2.85 (dd, J = 12.6, 7.2 Hz, 1 H, cis), 2.73 (dd, J = 12.6, 7.2 Hz, 1 H, cis), 2.68 (dd, J = 11.2, 8.3 Hz, 2 H, cis), 2.67-2.60 (m, 2 H, cis + trans), 2.63 (dd, J = 10.0, 5.0 Hz, 2 H, trans), 2.27-2.20 (m, 4 H, cis + trans), 2.08 (dd, J = 11.2, 9.0 Hz, 1 H, trans), 1.60-1.54 (m, 4 H, cis + trans), 1.21 (d, J = 7.6 Hz, 3 H, cis), 1.14 (d, J = 7.2 Hz, 3 H, trans), 1.07 (t, J = 7.6 Hz, 3 H, cis), 1.06 (t, J = 7.6 Hz, 3 H, trans). ^¹³C NMR (63 MHz, CDCl₃): δ = 217.7 (cis), 217.5 (trans), 208.1 (cis), 207.8 (trans), 138.2 (cis), 138.0 (trans), 128.9 (trans), 128.7 (cis), 128.4 (cis), 128.2 (trans), 127.5 (trans), 127.3 (cis), 66.4 (trans), 66.0 (cis), 59.4 (trans), 58.9 (cis), 57.9 (trans), 56.7 (cis), 45.2 (cis), 43.1 (trans), 41.9 (cis + trans), 36.2 (cis), 35.3 (trans), 18.0 (cis), 17.1 (cis), 17.0 (trans), 16.0 (cis), 13.7 (trans), 11.9 (trans). MS (EI, trans isomer): m/z (%) = 273 (5) [M⁺], 86 (40), 84 (61), 55 (55), 51 (35), 49 (100), 44 (49), 40 (90). MS (EI, cis isomer):
m/z (%) = 273 (4) [M⁺], 91 (100), 86 (41). HRMS (ES): m/z calcd for C₁₇H₂₄NO₂ [M + H]⁺: 274.18020; found: 274.18082.
(1 S ,2 S )-3-Benzyl-2-[2-(1-hydroxy-2-methylcyclopropyl)-ethyl]-3-azabicyclo[3.1.0]hexan-1-ol (13)
[Insepable mixture of undetermined cis and trans diastereomers (ratio 60:40: major a and minor b) on the side chain.] Colorless liquid. IR (neat): 3030, 2929, 2797, 1603 cm^-¹. ^¹H NMR (360 MHz, CDCl₃): δ = 7.34-7.26 (m, 10 H, a + b), 4.14 (d, J = 14.4 Hz, 1 H, b), 4.08 (d, J = 14.4 Hz, 1 H, b), 3.76 (d, J = 13.7 Hz, 1 H, a), 3.71 (d, J = 13.7 Hz, 1 H, a), 3.23 (dd, J = 12.6, 5.8 Hz, 1 H, b), 3.06 (dd, J = 9.7, 4.3 Hz, 1 H, a), 2.92 (t, J = 4.7 Hz, 1 H, a), 2.65 (t, J = 4.2 Hz, 1 H, b), 2.53 (d, J = 12.6 Hz, 1 H, b), 2.44 (d, J = 9.7 Hz, 1 H, a), 2.21-2.17 (m, 4 H, a + b), 2.06-1.97 (m, 4 H, a + b), 1.63-1.54 (m, 2 H, a + b), 1.44-1.39 (m, 2 H, a + b), 1.40 (t, J = 5.1 Hz, 1 H, a), 1.30-1.24 (m, 2 H, a + b), 1.26 (t, J = 5.8 Hz, 1 H, b), 1.18-1.08 (m, 2 H, a + b), 1.16 (d, J = 6.2 Hz, 3 H, a), 1.07 (d, J = 6.2 Hz, 3 H, b), 0.97-0.87 (m, 4 H, a + b), 0.81 (dd, J = 9.4, 5.1 Hz, 1 H, a), 0.07 (dd, J = 10.2, 5.8 Hz, 1 H, b). ^¹³C NMR (63 MHz, CDCl₃): δ = 139.7 (b), 137.9 (a), 129.6 (b), 128,7 (a), 128.5 (b), 128.3 (a), 128.2 (b), 127.5 (a), 70.2 (b), 70.1 (a), 65.7 (a), 64.6 (b), 57.8 (b), 57.7 (a), 55.8 (a), 55.7 (b), 54.1 (a), 53.4 (b), 37.3 (a), 31.1 (b), 24.6 (a), 24.5 (b), 22.7 (a), 22.1 (b), 20.2 (a), 18.4 (b), 17.4 (a), 16.5 (b), 14.4 (a), 13.8 (b), 12.4 (b), 11.4 (a). MS (EI, isomer a): m/z (%) = 287 (5)[M⁺], 218 (18), 200(20), 188(47), 91(100). MS (EI, isomer b): m/z (%) = 287 (6) [M⁺], 218 (17), 200(26), 188 (29), 91(100). HRMS (ES): m/z calcd for C₁₈H₂₆NO₂ [M + H]⁺: 288.19580; found: 288.19622.
(1 R ,2 S ) - 3-Benzyl-2-[2-(1-hydroxy-2-methylcyclo-propyl)ethyl]-3-azabicyclo[3.1.0]hexan-1-ol (14) [Inseparable mixture of undetermined cis and trans diastereomers (ratio 64:36: major a and minor b) on the
side chain.] Colourless liquid. IR (neat): 3036, 2929, 2791, 1602 cm^-¹. ^¹H NMR (360 MHz, CDCl₃): δ = 7.34-7.25 (m, 10 H, a + b), 3.84 (d, J = 13.3 Hz, 1 H, a), 3.83 (d, J = 13.3 Hz, 1 H, b), 3.64 (d, J = 13.3 Hz, 1 H, a), 3.63 (d, J = 13.3 Hz, 1 H, b), 3.17 (dd, J = 10.1, 4.7 Hz, 1 H, b), 3.02 (t, J = 4.2 Hz, 1 H, a), 2.97 (t, J = 4.2 Hz, 1 H, b), 2.34 (d, J = 9.4 Hz, 1 H, a), 2.31 (d, J = 10.1 Hz, 1 H, b), 2.29 (dd, J = 9.4, 4.0 Hz, 1 H, a), 2.01-1.92 (m, 4 H, a + b), 1.83-1.73 (m, 4 H, a + b), 1.59-1.54 (m, 2 H, a + b), 1.47-1.45 (m, 2 H, a + b), 1.29 (t, J = 6.7 Hz, 1 H, a), 1.28-1.25 (m, 2 H, a + b), 1.17 (dd, J = 9.0, 5.4 Hz, 1 H, b), 1.06 (d, J = 6.7 Hz, 3 H, a), 1.04 (d, J = 6.7 Hz, 3 H, b), 0.93 (dd, J = 9.0, 6.7 Hz, 1 H, a), 0.86-0.81 (m, 2 H, a + b), 0.76-0.73 (m, 4 H, a + b), 0.02 (t, J = 10.2 Hz, 1 H, b). ^¹³C NMR (63 MHz, CDCl₃): δ = 139.2 (b), 137.6 (a), 129.4 (a + b), 128,7 (b), 128.6 (a), 128.3 (b), 127.1 (a), 67.1 (b), 66.3 (a), 63.4 (a), 63.2 (b), 58.7 (a), 58.4 (b), 57.8 (a), 57.4 (b), 54.7 (b), 54.2 (a), 30.8 (a), 30.4 (b), 24.6 (a), 24.4 (b), 21.6 (a), 20.4 (b), 20.2 (a), 20.0 (b), 19.6 (a), 19.1 (b), 15.0 (a), 14.9 (b), 14.6 (b), 14.3 (a). MS (EI, isomer a): m/z (%) = 287 (9)[M⁺], 218 (21), 200 (23), 188 (22), 91 (100). MS (EI, isomer b): m/z (%) = 287(6) [M⁺], 218 (28), 200 (19), 188 (33), 91 (100). HRMS (ES): m/z calcd for C₁₈H₂₆NO₂ [M + H]⁺: 288.19580; found: 288.19653.