Enantioselective synthesis of bicylco[3.2.1]octan-8-ones using a tandem Michael-Henry reaction

Abstract

Bicyclo[3.2.1]octan-8-ones have been prepared from a tandem Michael-Henry reaction between cyclohexane-1,2-diones and nitroalkenes using a quinine-derived thiourea as the catalyst. Although four stereogenic centers were created during the reaction, only two diastereomers were obtained in good diastereoselectivity and high enantioselectivity (92-99% ee). When 3-methylcyclohexane-1,2-dione (R¹ = Me) was used as the substrate, only the regioisomeric product of the corresponding thermodynamic enolate was obtained.

1. Introduction

Although 1,2-diones are very reactive compounds,¹ they have been rarely studied in organocatalyzed reactions.² In 2006, we reported an organocatalyzed direct aldol reaction of 1,2-diones with ketones.^2c Most recently, Rueping and coworkers reported a tandem Michael-aldol reaction of cyclohexane-1,2-dione and α,β-unsaturated aldehydes.^2d We also demonstrated that this compound may be used for the synthesis of 8-oxo-5,6,7,8-tetrahydro-4H-chromene derivatives through a tandem Michael addition-cyclization reaction with benzylidenemalononitriles.^2e Although not well studied in organocatalysis, it appears that the dione may behave either as an ene-activator (for a Diels-Alder reaction),^2a an electrophile,^2b-c a nucleophile,^2e or both an electrophile and a nucleophile^2d in organocatalytic reactions. These multiple capacities warrant many potential applications of these interesting compounds in organocatalytic reactions.

On the other hand, tandem reactions have been the focus of current organic chemistry research because they can assemble complex molecule structures from relatively simple starting materials in a very efficient manner.³ This approach has also been widely used in organocatalysis in recent years,^4,5 and among the catalyst used for these organocatalyzed tandem reactions, cinchona alkaloid derivatives plays a crucial role.⁵ Herein we wish to report a novel tandem Michael-Henry reaction of the 1,2-dione compounds for the highly diastereoselective and enantioselective synthesis of bicylco[3.2.1]octan-8-ones, using a quinine-derived thiourea as the catalyst.

2. Results and Discussion

We recently demonstrated that a tandem Michael-Henry reaction may be achieved between 2-mercaptobezaldehydes and trans-β-nitrostyrenes,^4a in which 2-mercaptobezaldehyde acts as both a nucleophile and an electrophile. According to Rueping's results,^2d such a dual role may also be played by cyclohexane-1,2-dione. Thus, we envisioned that such a dione should be a good substrate for a tandem Michael-Henry reaction with trans-β-nitrostyrenes. Thus, cyclohexane-1,2-dione (1a) and trans-β-nitrostyrene (2a) were adopted as the model substrates to test our hypothesis. Since we and others⁶ have shown that cinchona alkaloid-derived thioureas⁷ are effective catalysts for a tandem Michael-aldol or Michael-Knoevenagel reactions, some thiourea derivatives (4-8) were adopted as the catalysts (Figure 1). For comparison purpose, similar catalysts (9-11) without the thiourea moiety are also included in the screening (Figure 1). The results of this screening are collected in Table 1.

Figure 1.

Structure of the catalysts applied in the screening [Ar = 3,5-(CF₃)₂C₆H₃].

Table 1.

Catalyst screening and reaction condition optimization^a

entry	solvent	catalyst	time (h)	drb	yieldc (%)	eed (%)
1	toluene	4	26	88:12	75	97
2	toluene	5	30	90:10	48	95
3	toluene	6	36	87:13	71	94e
4	toluene	7	28	90:10	60	95
5	toluene	8	25	91:9	59	93e
6	toluene	9	30	91:9	77	17
7	toluene	10	40	90:10	63	18
8	toluene	11	144	81:19	45	37
9	THF	4	48	74:26	46	97
10	ether	4	48	89:11	49	94
11	CH2Cl2	4	40	79:21	58	95
12	CHCl3	4	36	90:10	74	95
13	EtOAc	4	40	78:22	69	94
14	CH3CN	4	40	76:24	41	91
15	EtOH	4	32	92:8	72	90

^aUnless otherwise indicated, all reactions were conducted with trans-β-nitrostyrene (0.25 mmol), 1,2-cyclohexanedione (0.30 mmol), and the catalyst (15 mmol %) in the specified solvent (1.5 mL) at room temperature.

^bDiastereomeric ratio was determined by ¹H NMR analysis of the crude mixture.

^cYield of the isolated major diastereomer after column chromatography.

^dDetermined by HPLC analysis on a ChiralCel OJ-H column.

^eThe opposite enantiomer was obtained as the major product.

As shown in Table 1, when quinine-derived thiourea catalyst 4 was applied in toluene at room temperature for 26 h, a bicyclic product was obtained (entry 1). It should be pointed out that only two diastereomers (3a and 3aa) are present in the crude product according to the ¹H NMR spectrum, although four stereogenic centers are created during the reaction. The diastereomeric ratio is 88:12. Luckily the minor diastereomer 3aa may be easily removed by column chromatography, and the major diastereomer 3a was isolated in 75% yield and 97% ee (entry 1). Similarly, high ee values and good dr values may also be achieved with the other cinchona alkaloid-derived thiourea catalysts 5, 6, and 7 (entries 2-4), although the product yields obtained with catalysts 5 and 7 are lower due to the formation of some unidentified products in these cases. A trans-cyclohexane-1,2-diamine-derived thiourea catalyst 8 also leads to 59% yield of the product with excellent dr (91:9) and ee value (93%, entry 5). In contrast, similar cinchona alkaloid-derived catalysts without the thiourea moiety (9-11) all give very low ee values of the product, although the dr values remain high (entries 6-8). These results hint that the thiourea group is indeed essential for maintaining the high enantioselectivity of this reaction, most likely through hydrogen-bonding with trans-β-nitrostyrene. It should be pointed out that the major enantiomer obtained with catalysts 6 and 8 is opposite that of the rest of the catalysts.

Because catalyst 4 leads to the highest ee value of the product with a high dr value, it was adopted as the catalyst of choice in our further screening. Besides toluene, several other common organic solvents were screened. In fact, except for acetonitrile (entry 14) and ethanol (entry 15), in which the ee values obtained for the product are slightly lower, all the other solvents (THF, ether, CH₂Cl₂, CHCl₃, and EtOAc,) all lead to similar ee values of the product (around 95% ee, entries 9-13), although the yields of the product and/or the dr values are usually inferior to that obtained in toluene (entry 1). Thus, toluene was identified as the best solvent for this reaction.

Next, the scope and limitation of this reaction were studied. The results of this study are summarized in Table 2.

Table 2.

Tandem Michael-Henry reaction between 1,2-diones and nitroalkenes^a

entry	R1	R2	R3	R4	drb	yield (%)c	eed (%)
1	-(CH2)3-		H	Ph(3a)	88:12	75	97
2	-(CH2)3-		H	4-MeC6H4(3b)	92:8	83	97
3	-(CH2)3-		H	4-MeOC6H4(3C)	88:12	82	97
4	-(CH2)3-		H	4-ClC6H4(3d)	86:14	68	96
5	-(CH2)3-		H	4-BrC6H4(3e)	94:6	89	97
6	-(CH2)3-		H	4-CNC6H4(3f)	91:9	79	97e
7	-(CH2)3-		H	4-NO2C6H4(3g)	94:6	90	93e
8	-(CH2)3-		H	2-MeOC6H4(3h)	95:5	87	94
9	-(CH2)3-		H	2-BrC6H4(3i)	72:28	66	92
10	-(CH2)3-		H	3-ClC6H4(3j)	88:12	77	96e
11	-(CH2)3-		H		92:8	89	99e
12	-(CH2)3-		H	n-C6H13(3l)	88:12	77	97
13	-(CH2)3-		Me	Ph (3m)	88:12	67f	97
14	Me	H	H	Ph	---	0	---
15	-(CH2)2-		Me	Ph	---	0g	---

^aAll reactions were conducted with trans-nitroalkenes (0.25 mmol), 1,2-diones (0.30 mmol), and catalyst 4 (15 mmol %) in toluene (1.5 mL) at room temperature for 26 to 32 h (TLC monitoring).

^bDiastereomeric ratio was determined by 1H NMR analysis of the crude mixture.

^cYield of the isolated major diastereomer after column chromatography.

^dUnless otherwise specified, ee values were determined by HPLC analysis on a ChiralCel OJ-H column.

^eDetermined by HPLC analysis on a ChiralPak AD-H column.

^fThe reaction time was 72 h.

^gA complex mixture of unidentified products was obtained.

It is clear from the results in Table 2 that high dr values, excellent ee values, and good yields of the desired products may be obtained for the reaction of cyclohexane-1,2-dione and trans-β-nitrostyrenes with different substituents on the phenyl ring. For example, both electron-donating and electron-withdrawing groups at the para position of the phenyl ring do not lead to major differences in the dr values, the product yields, or the ee values (entries 1-7). Even with the strong electron-withdrawing nitro group, an excellent ee value of 93% and a high dr of 94:6 were obtained (entry 7). Similarly, substituents at the ortho (entries 8-9) or meta (entry 10) positions show no influence on the enantioselectivity, either. The lower dr value obtained with ortho-bromo-substituted nitrostyrene (entry 9) is probably due to steric reasons. A heteroarene-substituted nitroalkene (entry 11) is also a good substrate for this reaction: the reaction of trans-2-(2-nitrovinyl)thiophene with cyclohexane-1,2-dione produce the expected product in 89% yield and 99% ee. The original dr value was 92:8 in this case. Excellent ee value (97%), good dr value (88:12) and yield (77%) may also be obtained for a trans-nitroalkene with an alkyl substituent (entry 12).

3-Methylcyclohexane-1,2-dione (1b) is also a good substrate for this reaction (entry 13). Since this compound is not symmetric, it may enolize both at the less substituted 6 position (to give a kinetic enolate) or the more substituted 3 position (to give a thermodynamic enolate). However, only the thermodynamic enolate participates in the reaction to give a single regioisomer 3m with a dr of 88:12 as revealed by the NMR spectrum of the crude product. The major diastereomer may be isolated in 97% ee and 67% yield.

Nevertheless, this reaction seems to be limited to cyclohexane-1,2-diones, because the attempted reactions of both butane-2,3-dione and 3-methylcyclopentane-1,2-dione failed under the optimized conditions, with the former giving no sign of reaction at all (entry 14) and the latter being too complex to be useful (entry 15).

To determine the absolute configuration of the major enantiomer obtained in this reaction, crystals of compound 3f were analyzed by X-ray crystallography (Figure 2).⁸ On the basis of the X-ray analysis, its stereochemistry was assigned to be (1R,5R,6S,7S). The stereochemistry of the other products was similarly assigned on the basis of the reaction mechanism.

Figure 2.

ORTEP drawing of compound 3f

To show the practical utility of the current method, the reaction of compounds 1a and 2a was also carried out with a much larger scale (Eq. 1). As shown in Eq. 1, the reaction with 4 mmol (0.60 g) of 2a and 4.8 mmol (0.54 g) of 1a under the optimized conditions gave 0.77 g (74% yield) of 3a with an ee value of 96%, which is almost identical to the results obtained under the microscale conditions (Table 2, entry 1).

(Eq. 1)

3. Conclusions

We have demonstrated that bicyclo[3.2.1]otan-8-ones may be prepared in excellent enantioselectivity, high diastereoselectivity, and regioselectivity from a tandem Michael-Henry reaction between cyclohexane-1,2-diones and nitroalkenes by using a quinine-derived thiourea as the catalyst. However, cyclopentan-1,2-diones and enolizable acyclic 1,2-diones fail to give similar products.

4. Experimental

4.1. General

Unless otherwise specified, all compounds used in this study were purchased from commercial sources and were used as received. Catalysts 4,⁹ 5,⁹ 6,⁹ 7,⁹ 10,^7d and 11⁹ were prepared by using the reported procedures from quinine or quinidine. THF and ether were freshly distilled from benzophenone and sodium metal. Toluene, CH₂Cl₂, CHCl₃, and CH₃CN were distilled from CaH₂. HPLC grade EtOH and EtOAC were used directly. All reactions were carried out at ambient temperature in oven-dried glassware. Optical rotation was measured at room temperature (23 °C).

4.2. General Procedure for the Tandem Michael-Henry Reaction

To a solution of the 1,2-cycloalkanedione (0.30 mmol) and the catalyst (0.038 mmol, 15 mol %) in toluene (1.5 mL) was added the nitroalkene (0.25 mmol). The mixture was stirred at room temperature for the time as indicated in the Tables. The solvent was then removed under reduced pressure and the residue was purified by chromatography on silica gel to afford the product.

4.2.1. (1R,5R,6S,7S)-1-Hydroxy-7-nitro-6-phenylbicyclo[3.2.1]-octan-8-one (3a)

Colorless oil, 75% yield, [α]_D = –16.2 (c 0.455, CH₂Cl₁; ¹H NMR (300 MHz, CDCl₃): δ 7.13-7.16 (m, 2H), 7.24-7.36 (m, 3H), 4.78 (d, J = 6.0 Hz, 1H), 4.18 (d, J = 6.0 Hz, 1H), 3.34 (s, 1H), 2.81 (d, J = 2.7 Hz ,1H), 2.32-2.43 (m, 2H), 1.94-2.14 (m, 3H), 1.76-1.79 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 212.6, 142.5, 129.6, 128.1, 127.0, 93.9, 82.0, 52.0, 44.3, 40.2, 36.4, 18.4; ν_max (cm^-1): 3424, 1760, 1545; HRMS calcld. for C₁₄H₁₅NO₄: 261.1001; found: 261.1006. HPLC conditions: ChiralCel OJ-H column, i-PrOH/hexane 20:80, flow rate 1.0 mL/min, UV detection at 240 nm.

4.2.2 (1R,5R,6S,7S)-1-Hydroxy-6-(4-methylphenyl)-7-nitrobicyclo[3.2.1]octan-8-one (3b)

Colorless oil, 83% yield, [α]_D = –17.4 (c 0.465, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): δ 7.11-7.13 (dd, J₁ = 6.0 Hz, J₂ = 1.8 Hz, 2H), 7.01-7.04 (dd, J₁ = 6.0 Hz, J₂ = 1.8 Hz, 2H), 4.75 (d, J = 5.7 Hz, 1H), 4.13 (d, J = 5.7 Hz, 1H), 3.31 (s, 1H), 2.78 (d, J = 3.0 Hz, 1H), 2.32-2.42 (m, 2H), 2.30 (s, 3H), 1.95-2.14 (m, 3H), 1.74-1.77 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 212.7, 139.6, 137.8, 130.2, 126.8, 94.1, 81.9, 52.0, 43.9, 40.2, 36.4, 21.4, 18.3; ν_max (cm^-1): 3374, 2937, 1758, 1542; HRMS calcld. for C₁₅H₁₇NO₄: 275.1158; found: 275.1165. HPLC conditions: ChiralCel OJ-H column, i-PrOH/hexane 20:80, flow rate 1.0 mL/min, UV detection at 240 nm.

4.2.3. (1R,5R,6S,7S)-1-Hydroxy-6-(4-methoxyphenyl)-7-nitrobicyclo[3.2.1]octan-8-one (3c)

Colorless oil, 82% yield, [α]_D = –18.7 (c 1.58, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): δ 7.03-7.08 (dd, J₁ = 5.1 Hz, J₂ = 2.7 Hz, 2H), 6.82-6.87 (dd, J₁ = 5.1 Hz, J₂ = 2.7 Hz, 2H), 4.73 (d, J = 6.0 Hz, 1H), 4.12 (d, J = 6.0 Hz, 1H), 3.78 (s, 3H), 3.34 (s, 1H), 2.76 (d, J = 2.1 Hz, 1H), 2.31-2.42 (m, 2H), 1.92-2.12 (m, 3H), 1.74-1.77 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 212.9, 159.3, 135.7, 128.1, 115.0, 94.3, 81.9, 55.6, 52.1, 43.5, 40.0, 36.3, 18.2; ν_max (cm^-1): 3448, 2962, 1759; HRMS calcld. for C₁₅H₁₇NO₅: 291.1107; found:291.1098. HPLC conditions: ChiralCel OJ-H column, i-PrOH/hexane 20:80, flow rate 1.0 mL/min, UV detection at 220 nm.

4.2.4. (1R,5R,6S,7S)-6-(4-Chlorophenyl)-1-hydroxy-7-nitrobicyclo[3.2.1]octan-8-one (3d)

Viscous liquid, 68% yield, [α]_D = –18.4 (c 0.46, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): δ 7.01-7.08 (dd, J₁ = 6.6 Hz, J₂ = 1.8 Hz, 2H), 6.84-6.86 (dd, J₁ = 6.6 Hz, J₂ = 1.8 Hz, 2H), 4.46 (d, J = 6.0 Hz, 1H), 3.92 (d, J = 6.0 Hz, 1H), 3.04 (s, 1H), 2.54 (s, 1H), 2.08-2.20 (m, 2H), 1.68-1.91 (m, 3H), 1.51-1.57 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 212.2, 140.9, 134.1, 129.7, 128.3, 93.6, 81.9, 51.9, 43.7, 40.1, 36.4, 18.3; ν_max (cm^-1): 3440, 2938, 1745, 1544; HRMS calcld. for C₁₄H₁₄ClNO₄: 295.0611; found 295.0619. HPLC conditions: ChiralCel OJ-H column, i-PrOH/hexane 20:80, flow rate 1.0mL/min, UV detection at 240 nm.

4.2.5. (1R,5R,6S,7S)-6-(4-Bromophenyl)-1-hydroxy-7-nitrobicyclo[3.2.1]octan-8-one (3e)

White solid, 89% yield, mp: 139-140 °C, [α]_D = –15.7 (c 1.545, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): δ 7.44-7.48 (m, 2H), 7.01-7.05 (m, 2H), 4.70 (d, J = 5.7 Hz, 1H), 4.14 (d, J = 5.7 Hz, 1H), 3.29 (s, 1H), 2.77 (d, J = 2.1 Hz, 1H), 2.30-2.43 (m, 2H), 2.11-2.17 (m, 1H), 1.91-2.09 (m, 2H), 1.74-1.80 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 212.2, 141.4, 132.7, 128.7, 122.1, 93.5, 81.9, 51.8, 43.8, 40.1, 36.4, 18.3; ν_max (cm^-1): 3490, 3387, 1749, 1541; HRMS calcld. for C₁₄H₁₄BrNO₄: 339.0106; found:339.0103. HPLC conditions: ChiralCel OJ-H column, i-PrOH/hexane 20:80, flow rate 1.0mL/min, UV detection at 220 nm.

4.2.6. (1R,5R,6S,7S)-6-(4-Cyanophenyl)-1-hydroxy-7-nitrobicyclo[3.2.1]octan-8-one (3f)

White solid, 79% yield, mp: 207-209 °C, [α]_D = –16.9 (c 0.53, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃): δ 7.66-7.67 (dd, J₁ = 6.6 Hz, J₂ = 1.2 Hz, 2H), 7.28-7.32 (dd, J₁ = 6.6 Hz, J₂ = 1.2 Hz, 2H), 4.71 (d, J = 6.0 Hz, 1H), 4.24 (d, J = 6.0 Hz, 1H), 3.33 (s, 1H), 2.80-2.81 (m, 1H), 2.34-2.47 (m, 2H), 2.13-2.19 (m, 1H), 1.90-2.05 (m, 2H), 1.79-1.83 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): 211.8, 147.4, 133.5, 128.0, 118.3, 112.3, 92.9, 81.8, 51.5, 44.2, 40.0, 36.2, 18.1; ν_max (cm^-1): 3517, 2231, 1766, 1609; HRMS calcld. for C₁₅H₁₄N₂O₄:286.0954; found 286.0965. HPLC conditions: ChiralPak AD-H column, i-PrOH/hexane 35:65, flow rate 1.0mL/min, UV detection at 254 nm.

4.2.7. (1R,5R,6S,7S)-1-Hydroxy-7-nitro-6-(4-nitrophenyl)bicyclo[3.2.1]octan-8-one (3g)

White solid, 90% yield, mp: 170-171 °C, [α]_D = –11.3 (c 0.515, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃): δ 8.22-8.24 (dd, J₁ = 5.4 Hz, J₂ = 1.5 Hz, 2H), 7.36-7.38 (dd, J₁ = 5.4 Hz, J₂ = 1.5 Hz, 2H), 4.72 (d, J = 6.0 Hz, 1H), 4.31 (d, J = 6.0 Hz, 1H), 3.28 (s, 1H), 2.84 (d, J = 2.0 Hz, 1H), 2.45-2.49 (m, 1H), 2.36-2.39 (m, 1H), 2.14-2.21 (m, 1H), 1.90-2.05 (m, 2H), 1.81-1.85 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): 211.7, 149.3, 147.8, 128.2, 124.9, 92.8, 81.7, 51.5, 44.0, 40.0, 36.2, 18.2; ν_max (cm^-1): 1757, 1599, 1546; HRMS calcld. for C₁₄H₁₄N₂O₆: 306.0852; found: 306.0863. HPLC conditions: ChiralPak AD-H column, i-PrOH/hexane 35:65, flow rate 1.0 mL/min, UV detection at 254 nm.

4.2.8. (1R,5R,6S,7S)-1-Hydroxy-6-(2-methoxyphenyl)-7-nitrobicyclo[3.2.1]octan-8-one (3h)

Colorless oil, 87% yield, [α]_D = –13.8 (c 0.505, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): δ7.25-7.30 (m, 2H), 6.84-6.94 (m, 2H), 5.10 (d, J = 5.7 Hz, 1H), 4.06 (d, J = 5.7 Hz, 1H), 3.67-3.69 (m, 3H), 3.28 (s, 1H), 2.60(d, J = 3.9 Hz, 1H), 2.24-2.38 (m, 2H), 1.92-2.08 (m, 4H); ¹³C NMR (75 MHz, CDCl₃): δ 212.5, 156.0, 130.1, 129.4, 129.1, 120.7, 111.0, 91.9, 81.3, 54.2, 51.3, 43.7, 40.6, 36.5, 17.8; ν_max (cm^-1): 3451, 2937, 1761, 1543; HRMS calcld. for C₁₅H₁₇NO₅: 291.1107; found 291.1103. HPLC conditions: ChiralCel OJ-H column, i-PrOH/hexane 30:70, flow rate 1.0 mL/min, UV detection at 240 nm.

4.2.9. (1R,5R,6S,7S)-6-(2-Bromophenyl)-1-hydroxy-7-nitrobicyclo[3.2.1]octan-8-one (3i)

Viscous liquid, 66% yield, [α]_D = –11.6 (c 0.69, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): δ 7.58-7.61 (m, 1H), 7.28-7.33 (m, 1H), 7.12-7.17 (m, 1H), 6.98-7.02 (m, 1H), 5.08 (d, J = 6.0 Hz, 1H), 4.80 (d, J = 6.0 Hz, 1H), 3.28 (s, 1H), 2.64 (d, J = 3.9 Hz, 1H), 2.41-2.50 (m, 2H), 1.95-2.19 (m, 3H), 1.76-1.81 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 212.4, 140.9, 133.9, 129.6, 128.8, 128.4, 123.9, 92.1, 82.1, 52.8, 43.5, 40.6, 36.7, 18.3; ν_max (cm^-1): 3424, 2923, 1746, 1550; HRMS calcld. for C₁₄H₁₄BrNO₄: 339.0106; found 339.0120. HPLC conditions: ChiralCel OJ-H column, i-PrOH/hexane 20:80, flow rate 1.0 mL/min, UV detection at 220 nm.

4.2.10. (1R,5R,6S,7S)-6-(3-Chlorophenyl)-1-hydroxy-7-nitrobicyclo[3.2.1]octan-8-one (3j)

Colorless oil, 77% yield, [α]_D = –12.0 (c 0.755, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): δ 7.24-7.31 (m, 2H), 7.16 (s, 1H), 7.01-7.04 (m, 1H), 4.74 (d, J = 6.0 Hz, 1H), 4.16 (d, J = 6.0 Hz, 1H), 3.30 (s, 1H), 2.80 (d, J = 2.1 Hz, 1H), 2.30-2.45 (m, 2H), 2.10-2.19 (m, 1H), 1.90-2.08 (m, 2H), 1.75-1.81 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 212.0, 144.2, 135.4, 131.0, 128.4, 127.4, 125.0, 93.4, 81.9, 51.7, 44.0, 40.2, 36.4, 18.3; ν_max (cm^-1): 3418, 2961, 1759, 1596, 1544; HRMS calcld. for C₁₄H₁₄ClNO₄: 295.0611; found 295.0616. HPLC conditions: ChiralPak AD-H column, i-PrOH/hexane 35:65, flow rate 1.0 mL/min, UV detection at 254 nm.

4.2.11. (1R,5R,6R,7S)-1-Hydroxy-7-nitro-6-(thiophen-2-yl)bicyclo-[3.2.1]octan-8-one (3k)

Viscous oil, 89% yield, [δ]_D = –6.2 (c 1.30, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): δ 7.20-7.26 (m, 1H), 6.93-6.96 (m, 1H), 6.86-6.87 (m, 1H), 4.81 (d, J = 5.4 Hz, 1H), 4.48 (d, J = 5.4 Hz, 1H), 3.29 (s, 1H), 2.91-2.93 (m, 1H), 2.32-2.44 (m, 2H), 2.07-2.18 (m, 1H), 1.94-2.04 (m, 2H), 1.72-1.92 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 211.4, 144.8, 127.7, 125.3, 124.5, 94.1, 81.7, 52.4, 40.0, 39.7, 36.2, 18.3; ν_max (cm^-1): 3424, 2948, 1760, 1544; HRMS calcld. for C₁₂H₁₃NO₄S: 267.0565; found 267.0556. HPLC conditions: ChiralPak AD-H column, i-PrOH/hexane 40:60, flow rate 1.0 mL/min, UV detection at 254 nm.

4.2.12. (1R,5R,6R,7S)-6-Hexyl-1-hydroxy-7-nitrobicyclo[3.2.1]-octan-8-one (3l)

Colorless oil, 77% yield, [δ]_D = –43.5 (c 0.66, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃): δ 4.40 (d, J = 5.4 Hz, 1H), 3.22 (s, 1H), 2.91-2.98 (m, 1H), 2.32-2.40 (m, 2H), 2.14-2.18 (m, 1H), 1.70-2.07 (m, 3H), 1.61-1.67 (m, 1H), 1.40-1.50 (m, 2H), 1.20-1.29 (m, 8H), 0.86-0.90 (m, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 212.6, 92.2, 81.7, 50.0, 40.1, 39.0, 36.2, 36.0, 31.9, 29.3, 26.9, 22.9, 18.4, 14.4; ν_max (cm^-1): 3420, 2926, 2857, 1760, 1544; HRMS calcld. for C₁₄H₂₃NO₄: 269.1627; found 269.1616. HPLC conditions: ChiralCel OJ-H column, i-PrOH/hexane 20:80, flow rate 1.0 mL/min, UV detection at 220 nm.

4.2.13. (1R,5R,6R,7S)-1-Hydroxy-5-methyl-7-nitro-6-phenylbicyclo[3.2.1]octan-8-one (3m)

Colorless oil, 67% yield, [α]_D = –6.5 (c 0.94, CH₂Cl₂); ¹HNMR (300 MHz ,CDCl₃): δ 7.26-7.35 (m, 3H), 6.70-7.03 (m, 2H), 4.99 (d, J = 6.0 Hz, 1H), 4.13 (d, J = 6.0 Hz, 1H), 3.43 (s, 1H), 2.43-2.47 (m , 1H), 2.14-2.17 (m, 1H), 1.92-2.00 (m, 3H), 1.68-1.74 (m, 1H), 0.73 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ214.0, 139.9, 129.3, 128.6, 128.1, 93.7, 81.3, 51.5, 49.8, 45.5, 39.8, 18.4, 17.4; ν_max (cm^-1): 3426, 2931, 1756, 1545; HRMS calcld. for C₁₅H₁₇NO₄: 275.1158; found 275.1155. HPLC conditions: ChiralCel OJ-H column, i-PrOH/hexane 30:70, flow rate 1.0 mL/min, UV detection at 240 nm.