Regio- and Diastereoselective Synthesis and X-ray Structure

Article pubs.acs.org/jnp

Regio- and Diastereoselective Synthesis and X‑ray Structure Determination of (+)-2-Deoxyoryzalexin S from (+)-Podocarpic Acid. Structural Nonidentity with Its Nominal Natural Isolated Enantiomer Francesca Leonelli,*,† Valentina Latini,† Andrea Trombetta,† Gabriele Bartoli,† Francesca Ceccacci,† Angela La Bella,† Alessio Sferrazza,† Doriano Lamba,‡ Luisa M. Migneco,† and Rinaldo Marini Bettolo*,† †

Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le Aldo Moro, 5, I-00185 Roma, Italy Unità Organizzativa di Supporto, Sede di Trieste, Istituto di Crystallografia−CNR, Area Science Park-Basovizza, Strada Statale 14−Km 163.5, I-34149 Trieste, Italy

‡

S Supporting Information *

ABSTRACT: (+)-2-Deoxyoryzalexin S (1), the nominal enantiomer of a diterpenoid isolated in Chile from Calceolaria species, was regio- and diastereoselectively synthesized from (+)-podocarpic acid. (+)-2-Deoxyoryzalexin S (1) was characterized also as its acetyl derivative, (+)-2, whose structure was confirmed by X-ray crystallographic analysis. Surprisingly, comparison of the data recorded for (+)-1 and (+)-2 and those reported in the literature for the Calceolaria isolated diterpenoid 1 and its derivative (−)-2 showed some differences, suggesting that the latter do not possess the proposed structures.

I

n 1990 Garbarino and co-workers in Chile isolated a diterpenoid from some Calceolaria species1−3 to which, on the basis of the 1H and 13C spectra, the structure of 1 (2deoxyoryzalexin S) was attributed. To this compound, as well as to its congeners, the absolute ent-stemarane configuration was assigned on biogenetic grounds.1−3 Nominal 2-deoxyoryzalexin S (1) was characterized as its acetyl derivative (−)-2.1−3

(+)-podocarpic acid. The original isolated material is, in fact, no longer available for direct comparison (vide inf ra). The only stemarane diterpene compounds whose absolute configurations have been unambiguously established are (+)-stemarin (3), the parent compound of the stemarane family, whose structure and absolute configuration were established by X-ray diffraction,21 and (+)-13-stemarene (4),22,23 whose absolute configuration was confirmed by its preparation from (+)-podocarpic acid12 and (+)-stemarin (3).22

The fact that 1 and its congeners possess the ent-stemarane configuration, opposite that of the other known stemarane diterpenes, stimulated our interest for this class of compounds, whose structure and absolute configuration were never confirmed, neither by chemical correlation nor by X-ray diffraction. Thus, in the frame of our efforts in the synthesis of bicyclo[3.2.1]octane diterpene alkaloids 4−6 and diterpenoids,7−19 having now in hand a simple approach for the construction of the C/D ring system of the stemarane diterpenes,20 we decided to clarify this stereochemical aspect of Chilean stemarane diterpenes by synthesizing (+)-2deoxyoryzalexin S (1) from the preformed system of

The synthesis of (+)-1 would hopefully pave the way to the synthesis of the even more complex and biologically relevant (+)-oryzalexin S (5).24,25 Compound 5 is a phytoalexin, induced in rice leaves in response to the invasion of the fungus Pyricularia oryzae or when exposed to UV radiation or heavy metals.26

© 2012 American Chemical Society and American Society of Pharmacognosy

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RESULTS AND DISCUSSION The starting material was (−)-19-hydroxypodocarp-9-en-12one (7), available in four steps from (+)-podocarpic acid.27 Received: July 27, 2012 Published: October 23, 2012 1944

dx.doi.org/10.1021/np300518j | J. Nat. Prod. 2012, 75, 1944−1950

Journal of Natural Products

Article

Photoaddition of allene to (−)-7 in THF at −78 °C gave quantitatively the photoadduct (+)-8 (Scheme 1). NOESY

Scheme 2

Scheme 1

experiments showed a cross-peak between the H-C(11) and CH3-C(10), allowing us to establish the stereochemistry of the newly formed cyclobutane ring; the regiochemistry of the photoaddition followed from the downfield shift (about 1.5 ppm) of H-C(11), adjacent to both a double bond and a carbonyl function, compared to that of H2-C(13). Prior to methylation at C(13), the HO-C(19) photoadduct (+)-8 was protected as the tert-butyldimethylsilyl ether to give (+)-9. The protected photoadduct (+)-9 was then methylated with CH3I and NaHMDS/HMPA in THF at −78 °C. The methylated photoadduct 10 was then converted into the acetal 11, and the exocyclic methylene cleaved with OsO4/ NaIO4 to give the cyclobutanone 12 along with the unprotected keto-alcohol 13. The yield of the latter step was lowered by the formation of unidentified low Rf byproducts. The production of 13 during the OsO4/NaIO4 exocyclic double-bond cleavage was unexpected, although the cleavage of TBDMS ethers in the presence of other oxidants has been described.28 As far as the synthesis of (+)-1 is concerned, obtaining 13 was of no effect since the latter could be easily converted, via 14b, into 6-hydroxybicyclo[2.2.2]octan-2-one (15) (vide inf ra) by NaBH4 reduction and acid hydrolysis (Scheme 2). The stereochemical non-homogeneity at C(13) of compounds 10−12 is unimportant since it disappears when the bicyclo[2.2.2]octane system is formed. Compound 12 was then reduced with NaBH4 to give the cyclobutanol 14a. Treatment of 14a with a 2:1 THF/2 N HCl mixture gave 15 (Scheme 2) as an approximate 80:20 endo/exo epimeric mixture. This equilibrium distribution was explained by us in the past.29 The C(12) epimeric mixture of 15 dissolved in toluene was heated at 85 °C in the presence of TsOH, giving (+)-16 cleanly and in good yield. Thioacetalization of (+)-16 with ethanedithiol and BF3·Et2O at 0 °C then afforded (+)-17, which was transformed into (+)-1 by the action of Raney-Ni in EtOH at 60 °C (Scheme 3). Compound (+)-1 was fully characterized by means of 1H NMR, 13C NMR, COSY, HSQC, HMBC, DEPT 135, and NOESY experiments (Table 1).

Scheme 3

Comparison of the NMR data recorded by us for (+)-1 and those reported in the literature for 12,30,31 showed differences (Table 1) particularly in the 13C NMR regarding C(5), C(7), C(8), C(11), C(12), C(15), and C(16). (+)-2-Deoxyoryzalexin S was then acetylated with acetic anhydride in pyridine to give (+)-2 (Scheme 3). Compound (+)-2 was fully characterized by means of 1H NMR, 13C NMR, 1945



Article

Table 1. NMR Spectroscopic Data for (+)-1a and 1b (+)-1 δC, type

1

32.0, CH2d

2

18.4, CH2

3

35.6, CH2

4

38.7, Ce

5

50.2, CH

1.27−1.22, m

6

22.09, CH2

7

31.8, CH2d

8 9

44.4, CH 51.1, C

1.65−1.57, 1.36−1.31, 1.75−1.62, 1.22−1.12, 2.01−1.93,

10

38.8, Ce

11

30.0, CH2

12

43.3, CH

13

138.9, C

14

123.9, CH

δH (J in Hz) m m m m m m

m m m m m

1.66−1.60, m 1.49−1.43, m 2.19 t (4.4)

4.94 pd (4.3)

15

33.4, CH2

16

32.4, CH2

17

22.12, CH3

1.65−1.57, m 1.54−1.44, m 1.51−1.44, m 1.44−1.37, m 1.62, pt (1.3)

18 19

27.2, CH3 65.5, CH2

0.95, s 3.80, d (10.9)

17.9, CH3

3.41, dd (10.5, 1.0) 0.93, s

20

(+)-2

1

position

1.75−1.62, 1.22−1.12, 1.57−1.52, 1.48−1.41, 1.86−1.79, 0.95−0.85,

Table 2. NMR Spectroscopic Data for (+)-2a and (−)-2b

HMBCc

δC

δH (J in Hz)

position

δC, type

(−)-2

δH (J in Hz)

HMBCc

1.76−1.63, 1.23−1.12, 1.58−1.50, 1.47−1.40, 1.76−1.69, 0.99−0.89,

20

31.7

3

18.4

18, 19

36.1

3, 5, 18, 19 6, 7, 18, 19, 20 5, 7

36.8d 49.4

6

36.3

7, 14 7, 11, 12, 14 1, 2, 5, 20 8, 15

42.2 51.4

11, 14, 16, 17 8, 12, 16, 17 7, 8, 12, 17 11, 16

41.8

20

31.8

1

31.9, CH2d

3

18.3

2

18.4, CH2

18, 19

36.3

3

36.3, CH2

3, 5, 18, 19 6, 7, 18, 19, 20 5, 7

38.5d

4

37.2, C

49.4

5

50.2, CH

1.27−1.22, m

21.5

6

22.1, CH2

6

35.3

7

31.8, CH2d

7, 14 7, 11, 12, 14 1, 2, 5, 20 8, 15

42.2 51.4

8 9

44.3, CH 51.1, C

1.66−1.60, 1.41−1.35, 1.75−1.63, 1.23−1.12, 2.01−1.96,

38.2d

10

38.8, C

24.5

11

29.9, CH2

11, 14, 16, 17 8, 12, 16, 17 7, 8, 12, 17 11, 16

41.7

12

43.3, CH

138.6

13

138.9, C

14

123.9, CH

123.4

4.77 bs

m m m m m m

m m m m m

1.65−1.60, m 1.48−1.43, m 2.19 t (4.3)

4.94 pd (3.2)

34.2

15

33.4, CH2

11, 15

28.1

16

32.2, CH2

12, 14

21.8

17

22.1, CH3

1.65−1.58, m 1.52−1.44, m 1.52−1.45,m 1.44−1.37, m 1.62, pt (1.3)

5, 19 5, 18, 22

26.7 65.0

18 19

27.7, CH3 67.2, CH2

0.93, s 4.27, d (10.5)

1, 5

18.1

1.62, d (1.0) 0.97, s 3.78, d (11.0) 3.38, d (11.0) 0.93, s

δC

21.7

38.5d 24.6

138.4 123.2

20 21 22

H and 13C NMR at 400.13 and 100.61 MHz, respectively; δ in ppm relative to the residual solvent peak of CDCl3 at 7.26 and 77.0 ppm for 1 H and 13C, respectively. bThe data reported for 1 are those given in ref 2. 1H and 13C NMR at 250 and 63 MHz, respectively; δ in ppm relative to TMS as internal standard. cHMBC correlations, optimized for 8 Hz, are from carbons stated to the indicated protons. d,e Interchangeable within the same column.

17.9, CH3 171.6, C 21.2, CH3

0.96, s 2.04, s

4.77 bs

34.2

11, 15

28.1

12, 14

22.0

5, 19 5, 18, 22

27.3 66.8

1, 5 19, 22

18.0 171.1 21.0

3.87, d (10.5)

a1

δH (J in Hz)

1.63, d (1.0) 0.93, s 4.28, d (11.0) 3.84, d (11.0) 1.02, s 2.03, s

H and 13C NMR at 400.13 and 100.61 MHz, respectively; δ in ppm relative to the residual solvent peak of CDCl3 at 7.26 and 77.0 ppm for 1 H and 13C, respectively. bThe data reported for (−)-2 are those given in ref 2. 1H and 13C NMR at 250 and 63 MHz, respectively; δ in ppm relative to TMS as internal standard. cHMBC correlations, optimized for 8 Hz, are from carbons stated to the indicated protons. d Interchangeable within the same column. a1

COSY, HSQC, HMBC, DEPT 135, and NOESY (Table 2). Comparison of the NMR data recorded by us for (+)-2 and those reported in the literature for (−)-21−3,30 showed differences (Table 2) particularly in the 13C NMR regarding C(5), C(7), C(8), C(11), C(12), C(15), and C(16). The melting points [(+)-2: 118.2−119.7 °C; (−)-2: 96−97 °C] and the specific rotations [[α]25D: (+)-2 +58.2 (c 1.2, CHCl3); (−)-2 −17.02 (c 2.0, CHCl3)] were also not identical. The structure of (+)-2 (crystals from EtOH/H2O) was also unambiguously confirmed by X-ray crystallographic analysis using synchrotron radiation data collected at ELETTRA (XRD1 beamline), Trieste (Figure 1).32 These differences may not be attributed to an epimer at C(4) since the data of compound 6, obtained by Coates and co-

Figure 1. X-ray structure of (+)-2. Thermal ellipsoids are shown at the 50% probability level. 1946



Article

workers22 from (+)-stemarin (3), are also different from those recorded for the nominal compound 1, isolated from Calceolaria species.33 In conclusion, the first synthesis of (+)-2-deoxyorizalexin S (1) from (+)-podocarpic acid was achieved. (+)-2-Deoxyorizalexin S (1) was characterized also as its acetyl derivative (+)-2. The structure of (+)-2 was confirmed by X-ray crystallographic analysis. Comparison of the data of (+)-1 and (+)-2 with those reported in the literature for 1 and (−)-2 did not confirm the structure of (−)-2-deoxyorizalexin S originally assigned to the diterpenoid isolated from Chilean Calceolaria species. Further structural work on Chilean Calceolaria diterpenoids, to which nominal structures 1 and 6 were attributed, respectively, appears, therefore, necessary.

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3.55−3.49 (1H, m), 3.37 (1H, d, J = 9.6 Hz), 2.52 (1H, A of ABX2, JAB = 17.5 Hz, JAX2 = 2.7 Hz), 2.47 (1H, dd, J = 5.6 Hz, J = 18.8 Hz), 2.30 (1H, B of ABYX2, JAB = 17.5 Hz, JBY = 3.1 Hz, JBX2 = 2.7 Hz), 2.05− 1.86 (2H, m), 1.66−1.04 (10H, m), 0.99 (9H, s), 0.97 (3H, s), 0.92− 0.71 (3H, m), 0.64 (3H, s), −0.07 (6H, s); 13C NMR (C6D6, 100.61 MHz) δ 208.1, 141.7, 109.2 (CH2), 65.1 (CH2), 55.6 (CH), 49.7, 47.1 (CH), 39.1, 38.6 (CH2), 38.5, 36.5 (CH), 36.0 (CH2), 31.7 (CH2), 31.5 (CH2), 29.2 (CH2), 27.6 (CH3), 26.2 (3xCH3), 25.5 (CH2), 22.2 (CH2), 18.6, 18.4 (CH2), 16.5 (CH3), −5.29 (CH3), −5.33 (CH3); GC-MS m/z 359 [M − (C4H9)]+ (9), 269 (10), 187 (11), 173 (19), 159 (12), 145 (12), 131 (13), 119 (12), 105 (16), 89 (22), 75 (100), 67 (12), 55 (27); HRESIMS m/z 439.3021 (calcd for C26H44O2Si [M + Na]+, 439.3008). Preparation of 10 from (+)-9. A solution of sodium bis(trimethylsilyl)amide (NaHMDS, 17 mL, 1 M in THF, 17 mmol) was added at −78 °C to a solution of (+)-9 (7.0 g, 17 mmol) in THF (43 mL). After 1 h the resulting sodium enolate was added to a solution of CH3I (2.0 mL, 33 mmol) in hexamethylphosphoramide (HMPA, 8.7 mL, 50 mmol). The solution was stirred at −78 °C until TLC showed the disappearance of (+)-9 (4 h). The mixture was warmed to rt, neutralized with 2 N HCl, diluted with Et2O, washed, dried, and evaporated. The residue was purified by CC (AcOEt/n-hexane, 2.5:97.5) to give a mixture of 10a and 10b (6.2 g, 14 mmol, 82%, 10a:10b, 3:1; Rf 10a > Rf 10b). For analytical purposes the mixture was separated by HPLC (AcOEt/n-hexane, 1:99): (+)-10a: white powder, mp 106.7−108.0 °C; [α]25D +21.9 (c 3.1, CCl4); IR (CCl4) νmax 1699; 1H NMR (C6D6, 300.13 MHz) δ 4.90 (1H, pq, J = 2.6 Hz), 4.81 (1H, pq, J = 2.5 Hz), 3.58 (1H, A of AB, JAB = 9.6 Hz), 3.56 (1H, pq, J = 2.8 Hz), 3.36 (1H, B of AB, JAB = 9.6 Hz), 2.66−2.45 (2H, m), 2.33 (1H, dq, Jd = 17.4 Hz, Jq = 2.7 Hz), 2.07−1.87 (2H, m), 1.66− 0.68 (27H, m), 0.64 (3H, s), 0.07 (6H, s); 13C NMR (C6D6, 75.48 MHz) δ 212.5, 142.2, 109.3 (CH2), 64.9 (CH2), 55.9 (CH), 51.2, 47.0 (CH), 39.4 (CH), 39.2, 38.5, 35.8 (CH2), 34.3 (CH2), 32.7 (CH), 31.8 (CH2), 31.0 (CH2), 29.2 (CH2), 27.5 (CH3), 26.2 (3×CH3), 22.0 (CH2), 18.6, 18.4 (CH2), 17.6 (CH3), 16.3 (CH3), −5.29 (CH3), −5.33 (CH3); GC-MS m/z 373 [M − (C4H9)]+ (7), 283 (10), 187 (15), 173 (14), 159 (12), 145 (15), 131 (10), 119 (15), 105 (17), 89 (25), 81 (18), 75 (100), 67 (14), 55 (24); HRESIMS m/z 453.3143 (calcd for C27H46O2Si [M + Na]+, 453.3165); (−)-10b: white solid, mp 150.3−151.7 °C; [α]25D −8.3 (c 4.8, CCl4); IR (CCl4) νmax 1697; 1 H NMR (C6D6, 400.13 MHz) δ 5.07 (1H, q, J = 2.8 Hz), 4.82 (1H, pq, J = 2.6 Hz), 3.64 (1H, d, J = 9.6 Hz), 3.55−3.50 (1H, m), 3.40 (1H, d, J = 9.6 Hz), 2.51 (1H, A of ABX2, JAB = 17.4 Hz, JAX2 = 2.5 Hz), 2.31 (1H, B of ABYX2, JAB = 17.4 Hz, JBY = 3.1 Hz, JBX2 = 2.7 Hz), 1.97−1.84 (2H, m), 1.61−1.10 (13H, m), 1.00 (9H, s), 0.99 (3H, s), 0.94−0.71 (3H, m), 0.65 (3H, s), 0.08 (6H, s); 13C NMR (C6D6, 100.61 MHz) δ 209.9, 141.6, 109.4 (CH2), 65.1 (CH2), 55.2 (CH), 49.6, 47.1 (CH), 45.5 (CH), 39.0, 38.6, 36.8 (CH), 36.0 (CH2), 34.2 (CH2), 31.84 (CH2), 31.78 (CH2), 29.1 (CH2), 27.6 (CH3), 26.2 (3xCH3), 22.3 (CH2), 19.1 (CH3), 18.6, 18.4 (CH2), 16.6 (CH3), −5.29 (CH3), −5.32 (CH3); GC-MS m/z 373 [M − (C4H9)]+ (10), 285 (11), 187 (16), 173 (13), 159 (10), 145 (16), 119 (14), 105 (16), 89 (19), 81 (16), 75 (100), 67 (13), 55 (23); HRESIMS m/z 453.3186 (calcd for C27H46O2Si [M + Na]+, 453.3165). Preparation of 11 from 10. A solution of 10 (6.1 g, 14 mmol), ethane-1,2-diol (38 mL, 0.55 mol), and TsOH (0.13 g, 0.71 mmol) in benzene (0.60 L) was placed into a two-neck flask fitted with a Dean− Stark apparatus, a condenser, and a CaCl2 tube. The mixture was refluxed until TLC showed the disappearance of 10 (24 h). After cooling to rt, the mixture was diluted with Et2O, washed with a saturated NaHCO3 solution, dried, and evaporated. CC (Et2O/nhexane, 2:98) yielded a mixture of 11a and 11b (5.2 g, 11 mmol, 78%, 11a:11b, 1:9; Rf 11a > Rf 11b). For analytical purposes the mixture was separated by HPLC (AcOEt/n-hexane, 0.5:99.5): (−)-11a: white solid, mp 117.3−118.3 °C; [α]25D −42.8 (c 1.3, CHCl3); 1H NMR (C6D6, 400.13 MHz) δ 5.51−5.47 (1H, m), 5.01−4.97 (1H, m), 3.82 (1H, d, J = 9.6 Hz), 3.58−3.43 (5H, m), 2.96 (1H, bs), 2.52 (1H, A of ABX2, JAB = 17.3 Hz, JAX2 = 2.4 Hz), 2.46 (1H, B of ABYX2, JAB = 17.3 Hz, JBY = 2.8 Hz, JBX2 = 2.7 Hz), 2.16−1.98 (3H, m), 1.71−1.25 (12H, m), 1.11 (3H, s), 1.05 (3H, s), 1.03−0.82 (12H, m), 0.094 (3H, s),

EXPERIMENTAL SECTION

General Experimental Procedures. All solvents were analytical grade. All organic solutions, except where differently indicated, were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. Yields were not optimized. TsOH was the monohydrate. TLC: silica gel 60 F254. Column chromatography (CC): silica gel 60, 70−230 mesh ASTM. Melting points: Mettler-FP-61 (uncorrected). IR spectra: ShimadzuFTIR 8400 S infrared spectrophotometer. 1H and 13C NMR spectra (compound 10a): Bruker AC 300 at 300.13 and 75.48 MHz, respectively; δ in ppm relative to the residual solvent peak of C6D6 at 7.15 and 128.02 ppm and CDCl3 at 7.26 and 77.0 ppm for 1H and 13 C, respectively. 1H and 13C NMR (compounds 1, 2, 8−9, 10b, 11− 13, 15−17): Bruker AVANCE 400 at 400.13 and 100.61 MHz, respectively; δ in ppm relative to the residual solvent peak of C6D6 at 7.15 and 128.02 ppm and CDCl3 at 7.26 and 77.0 ppm for 1H and 13C, respectively; J in Hz. HPLC analysis: Shimadzu LC-10AD; RID detector; analytical columns, EC 250/4 Nucleosil 100-5, EC 250/4 Nucleodur 100-5; flow rate of 0.8 mL/min; semipreparative column, VP 250/10 Nucleodur 100-5; flow rate of 6 mL/min. GC-MS analysis: Shimadzu GCMS-QP5000. Optical rotations: DIP 370 Jasco digital polarimeter. HRESIMS spectra: Micromass Q-TOF Micromass spectrometer (Waters) in the electrospray-ionization mode. Preparation of (+)-8 from (−)-7. A Pyrex vessel containing a solution of (−)-7 (6.9 g, 26 mmol) in THF (78 mL) was cooled at −78 °C, and an excess of allene was condensed into it. The vessel was irradiated under Ar at −78 °C with a 500 W mercury vapor lamp until TLC showed the disappearance of (−)-7 (4 h). The solution was slowly warmed to rt, the solvent evaporated, and the residue purified by CC (AcOEt/n-hexane, 3.5:6.5) to give (+)-8 (6.3 g, 21 mmol, 81%): white powder, mp 174.2−175.8 °C; [α]25D +27.4 (c 3.2, CHCl3); IR (CHCl3) νmax 1686; 1H NMR (CDCl3, 400.13 MHz) δ 4.91 (1H, pq, J = 2.6 Hz), 4.89 (1H, pq, J = 2.8 Hz), 3.72 (1H, d, J = 10.8 Hz), 3.47−3.42 (1H, m), 3.40 (1H, d, J = 10.8 Hz), 2.79 (1H, dt, Jt = 2.5 Hz, Jd = 17.4 Hz), 2.63−2.51 (2H, m), 2.14 (1H, dddd, J = 0.8 Hz, J = 7.7 Hz, J = 11.5 Hz, J = 19.1 Hz), 1.95−1.25 (12H, m), 1.11 (1H, qd, Jd = 4.5 Hz, Jq = 12.7 Hz), 1.03 (1H, dd, J = 2.9 Hz, J = 12.9 Hz), 0.94 (3H, s), 0.89 (1H, td, Jd = 4.4 Hz, Jt = 13.7 Hz), 0.81 (3H, s); 13C NMR (CDCl3, 100.61 MHz) δ 211.4, 140.8, 109.7 (CH2), 64.8 (CH2), 55.6 (CH), 49.7, 47.2 (CH), 39.1, 38.5 (CH2), 38.2, 36.5 (CH), 35.4 (CH2), 31.7 (CH2), 31.6 (CH2), 28.9 (CH2), 26.8 (CH3), 25.3 (CH2), 21.9 (CH2), 18.1 (CH2), 16.7 (CH3); HRESIMS m/z 325.2159 (calcd for C20H30O2 [M + Na]+, 325.2144). Preparation of (+)-9 from (+)-8. tert-Butyldimethylsilyl chloride (TBDMSCl, 7.7 g, 51 mmol) and imidazole (3.1 g, 45 mmol) were added to a solution of (+)-8 (5.9 g, 19 mmol) in anhydrous THF (20 mL). The mixture was stirred at rt until TLC showed the disappearance of (+)-8 (5 h). n-Hexane was added, the suspension filtered through Celite, the organic phase evaporated, and the residue purified by CC (AcOEt/n-hexane, 2.5:97.5) to give (+)-9 (7.2 g, 17 mol, 89%): white powder, mp 114.6−116.3 °C; [α]25D +9.0 (c 3.1, CCl4); IR (CCl4) νmax 1697; 1H NMR (C6D6, 400.13 MHz) δ 5.02 (1H, q, J = 2.7 Hz), 4.82 (1H, q, J = 2.6 Hz), 3.63 (1H, d, J = 9.6 Hz), 1947



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0.091 (3H, s); 13C NMR (C6D6, 100.61 MHz) δ 144.4 (CH2), 111.4, 109.5, 65.2 (CH2), 64.4 (CH2), 63.5 (CH2), 49.2, 47.5 (CH), 47.2 (CH), 39.4 (CH), 39.0, 38.7, 36.0 (CH2), 35.7 (CH2), 32.5 (CH), 32.2 (CH2), 31.1 (CH2), 29.6 (CH2), 27.7 (CH3), 26.2 (3×CH3), 22.3 (CH2), 20.3 (CH3), 18.7 (CH2), 18.6, 16.5 (CH3), −5.25 (CH3), −5.31 (CH3); GC-MS m/z 474 [M]+ (7), 329 (13), 205 (9), 113 (100), 100 (7), 75 (29), 69 (13), 55 (9); HRESIMS m/z 497.3450 (calcd for C29H50O3Si [M + Na]+, 497.3427); (+)-11b: white solid, mp 80.6−81.8 °C; [α]25D +27.2 (c 4.5, CHCl3); 1H NMR (C6D6, 400.13 MHz) δ 5.37−5.31 (1H, m), 5.02−4.97 (1H, m), 3.79 (1H, d, J = 9.6 Hz), 3.64−3.50 (4H, m), 3.44 (1H, d, J = 9.6 Hz), 2.83−2.79 (1H, m), 2.51−2.35 (3H, m), 2.16−1.98 (2H, m), 1.67−1.35 (7H, m), 1.31−1.15 (2H, m), 1.08−0.99 (16H, m), 0.97 (3H, s), 0.95−0.68 (2H, m), 0.093 (3H, s), 0.087 (3H, s); 13C NMR (C6D6, 100.61 MHz) δ 146.1, 113.5, 108.9 (CH2), 65.3 (CH2), 65.2 (CH2), 64.7 (CH2), 49.7, 48.2 (CH), 47.6 (CH), 39.2, 38.6, 36.0 (CH2), 35.8 (CH2), 31.9 (CH2), 31.3 (CH), 30.9 (CH2), 30.64 (CH), 30.59 (CH2), 27.7 (CH3), 26.2 (3×CH3), 22.3 (CH2), 18.6 (CH2), 16.1 (CH3), 15.9 (CH3), −5.25 (CH3), −5.29 (CH3); GC-MS m/z 474 [M]+ (7), 329 (14), 205 (9), 113 (100), 100 (9), 89 (7), 73 (41), 69 (14), 55 (9); HRESIMS m/z 497.3423 (calcd for C29H50O3Si [M + Na]+, 497.3427). Preparation of 12 and 13 from 11. A solution of OsO4 (43 mg, 0.17 mmol), pyridine (1.0 mL), and H2O (9 mL) was treated with a solution of 11 (4.1 g, 8.6 mmol) in THF (121 mL). After stirring in the dark for 10 min, the solution was treated with a suspension of NaIO4 (21 g, 98 mmol) in H2O (65 mL), and the resulting mixture stirred until TLC showed the disappearance of 11 (92 h). The suspension was filtered through Celite, the filtrate diluted with Et2O, and the organic phase washed, dried, and evaporated. The residue was purified by CC (AcOEt/n-hexane, 1:9) to give 12 (1.7 g, 3.6 mmol) as a mixture of 12a and 12b (12a:12b, 1:9; Rf 12a > Rf 12b) and 13 (0.56 g, 1.5 mmol). Yield: 59%. (−)-12a: white solid, mp 141.0−142.3 °C; [α]25D −3.0 (c 1.9, CHCl3); IR (CHCl3) νmax 1773; 1H NMR (C6D6, 400.13 MHz) δ 3.98 (1H, pq, J = 7.4 Hz), 3.76 (1H, td, Jd = 4.2 Hz, Jt = 6.8 Hz), 3.66−3.57 (2H, m), 3.46−3.34 (2H, m), 3.03 (1H, d, J = 16.3 Hz), 3.00 (1H, d, J = 6.7 Hz), 2.54 (1H, dd, J = 6.7 Hz, J = 16.3 Hz), 1.83 (1H, pd, J = 13.5 Hz), 1.71−1.51 (3H, m), 1.46−1.04 (9H, m), 0.98 (9H, s), 0.97 (3H, s), 0.94 (3H, s), 0.81 (3H, s), 0.78−0.64 (2H, m) 0.07 (3H, s), 0.06 (3H, s); 13C NMR (C6D6, 100.61 MHz) δ 202.9, 110.1, 67.1 (CH), 65.9 (CH2), 65.1 (CH2), 65.0 (CH2), 48.0 (CH), 47.1 (CH2), 46.6, 40.6 (CH), 40.2, 38.7, 36.5 (CH), 35.9 (CH2), 34.4 (CH2), 32.5 (CH2), 30.5 (CH2), 27.7 (CH3), 26.2 (3×CH3), 23.0 (CH2), 18.6, 18.5 (CH2), 17.1 (CH3), 14.6 (CH3), −5.30 (CH3), −5.32 (CH3); GC-MS m/z 476 [M]+ (5), 207 (5), 147 (5), 134 (33), 119 (9), 113 (37), 105 (8), 100 (6), 87 (100), 81 (9), 75 (51), 69 (12), 55 (12); HRESIMS m/z 499.3241 (calcd for C28H48O4Si [M + Na]+, 499.3220). (+)-12b: white solid, mp 101.6− 103.0 °C; [α]25D +34.1 (c 2.9, CHCl3); IR (CHCl3) νmax 1769; 1H NMR (C6D6, 400.13 MHz) δ 3.69 (1H, d, J = 9.6 Hz), 3.65−3.57 (1H, m), 3.54−3.41 (3H, m), 3.39 (1H, d, J = 9.6 Hz), 3.04−2.99 (1H, m), 2.67 (1H, A of ABX, JAB = 18.4 Hz, JAX = 4.6 Hz), 2.59 (1H, B of ABX, JAB = 18.4 Hz, JBX = 2.1 Hz), 2.22−2.09 (1H, m), 1.97−1.78 (2H, m), 1.57−1.35 (3H, m), 1.33−1.06 (6H, m), 0.99 (9H, s), 0.98 (3H, s), 0.96−0.95 (1H, m), 0.94 (3H, d, J = 6.6 Hz), 0.89 (3H, s), 0.74 (1H, td, Jd = 3.8 Hz, Jt = 13.6 Hz), 0.61 (1H, qd, Jd = 4.2 Hz, Jq = 12.8 Hz), 0.07 (6H, s); 13C NMR (C6D6, 100.61 MHz) δ 204.8, 111.2, 65.02 (CH2), 65.00 (CH2), 64.0 (CH), 48.4 (CH), 47.0 (CH2), 46.5, 39.2, 38.5, 35.8 (CH2), 35.1 (CH2), 33.9 (CH), 31.6 (CH2), 31.3 (CH2), 30.1 (CH), 27.6 (CH3), 26.2 (3xCH3), 22.3 (CH2), 18.6, 18.3 (CH2), 16.6 (CH3), 15.5 (CH3), −5.30 (CH3), −5.34 (CH3); GC-MS m/z 476 [M]+ (1), 377 (4), 147 (6), 134 (29), 121 (5), 113 (66), 105 (8), 100 (6), 93 (7), 87 (100), 81 (7), 75 (49), 69 (11), 55 (11); HRESIMS m/z 499.3221 (calcd for C28H48O4Si [M + Na]+, 499.3220). (+)-13: white solid, mp 207.6−209.3 °C; [α]25D +51.4 (c 2.8, CHCl3); IR (CHCl3) νmax 1769; 1H NMR (CDCl3, 400.13 MHz) δ 4.10−3.83 (4H, m), 3.76 (1H, d, J = 10.9 Hz), 3.41 (1H, d, J = 10.9 Hz), 3.05 (1H, bs), 2.89 (1H, A of ABX, JAB = 19.1 Hz, JAX = 4.0 Hz), 2.83 (1H, B of AB, JAB = 19.1 Hz), 2.28−2.15 (1H, m), 1.90−1.17 (12H, m), 1.09 (1H, d, J = 12.5 Hz), 0.98 (3H, s), 0.94 (3H, s), 0.91−

0,79 (5H, m); 13C NMR (CDCl3, 100.61 MHz) δ 208.6, 110.9, 65.3 (CH2), 64.7 (CH2), 63.9 (CH), 48.5 (CH), 46.8 (CH2), 46.5, 39.0, 38.2, 35.3 (CH2), 34.8 (CH2), 33.8 (CH), 31.5 (CH2), 31.1 (CH2), 30.0 (CH), 26.8 (CH3), 21.9 (CH2), 17.9 (CH2), 16.5 (CH3), 15.3 (CH3); GC-MS m/z 362 [M]+ (0.3), 278 (5), 134 (24), 119 (7), 113 (88), 100 (13), 91 (14), 87 (100), 79 (12), 69 (14), 55 (19); HRESIMS m/z 385.2370 (calcd for C22H34O4 [M + Na]+, 385.2355). Preparation of 15 from 12. A solution of 12 (1.2 g, 2.5 mmol) in Et2O/MeOH (1:1; 51 mL) was treated with NaBH4 (0.49 g, 13 mmol) at 0 °C, and the mixture stirred until TLC showed the disappearance of 12 (20 min). H2O was added slowly at 0 °C to quench excess NaBH4. After neutralization with 2 N HCl the solution was diluted with Et2O, washed, dried, and evaporated to give 14a (1.2 g). A solution of the crude 14a (1.2 g) in THF/2 N HCl (4:1; 210 mL) was refluxed until TLC showed the disappearance of 14a (7 h). After cooling to rt, the whole was diluted with AcOEt, washed with saturated NaHCO3 and brine, dried, and evaporated. The residue was subjected to CC (AcOEt/n-hexane, 1:3) to give 15 (0.72 g, 2.2 mmol, 88%) as a mixture of 15a and 15b (15a:15b, 82:18; Rf 15a < Rf 15b), which for analytical purposes was separated by CC. (+)-15a: white powder, mp 191.0−192.3 °C; [α]25D +13.7 (c 2.9, CHCl3); IR (CHCl3) νmax 1715; 1 H NMR (CDCl3, 400.13 MHz) δ 3.84−3.77 (2H, m), 3.44 (1H, d, J = 10.7 Hz), 2.61 (1H, ddd, J = 3.0 Hz, J = 9.2 Hz, J = 14.1 Hz), 2.15 (1H, A of AB, JAB = 18.5 Hz), 2.11 (1H, B of ABX, JAB = 18.5 Hz, JBX = 3.1 Hz), 1.91−1.61 (7H, m), 1.54−1.11 (8H, m), 0.99 (3H, s), 0.98 (3H, s), 0.97−0.85 (5H, m); 13C NMR (CDCl3, 100.61 MHz) δ 216.0, 74.1 (CH), 65.5 (CH2), 48.9, 47.5 (CH), 44.3 (CH2), 43.4, 38.63, 38.58, 37.8 (CH2), 35.5 (CH2), 33.6 (CH2), 33.1 (CH2), 32.96 (CH), 32.95 (CH2), 27.6 (CH3), 22.1 (CH2), 18.5 (CH2), 17.4 (CH3), 16.1 (CH3); GC-MS m/z 320 [M]+ (5), 289 (25), 276 (25), 260 (32), 253 (11), 245 (13), 229 (17), 207 (11), 173 (11), 161 (21), 147 (26), 135 (38), 123 (93), 105 (73), 91 (65), 81 (96), 67 (70), 55 (100); HRESIMS m/z 343.2232 (calcd for C20H32O3 [M + Na]+, 343.2249). (+)-15b: white powder, mp 184.5−186.5 °C; [α]25D +37.1 (c 3.0, CHCl3); IR (CHCl3) νmax 1715; 1H NMR (CDCl3, 400.13 MHz) δ 3.81 (1H, d, J = 10.8 Hz), 3.74−3.67 (1H, m), 3.45 (1H, d, J = 10.8 Hz), 2.14−1.79 (6H, m), 1.77−1.22 (13H, m), 0.98 (3H, s), 0.96 (3H, s), 0.93−0.84 (4H, m); 13C NMR (CDCl3, 100.61 MHz) δ 216.9, 70.5 (CH), 65.5 (CH2), 49.1, 47.2 (CH), 44.3 (CH2), 42.4, 38.7, 38.6, 35.5 (CH2), 33.2 (CH2), 33.1 (CH), 32.6 (CH2), 31.8 (CH2), 31.6 (CH2), 27.5 (CH3), 22.2 (CH2), 18.5 (CH2), 17.1 (CH3), 15.9 (CH3); GC-MS m/z 320 [M]+ (6), 289 (24), 276 (13), 271 (30), 229 (19), 173 (10), 159 (20), 147 (27), 135 (19), 123 (100), 121 (33), 105 (52), 91 (48), 81 (67), 69 (40), 55 (71); HRESIMS m/z 343.2256 (calcd for C20H32O3 [M + Na]+, 343.2249). Preparation of 15 from (+)-13. A solution of 13 (0.31 g, 0.87 mmol) in Et2O/MeOH (1:1; 18 mL) was treated with NaBH4 (0.16 g, 4.2 mmol) at 0 °C, and the mixture stirred until TLC showed the disappearance of (+)-13 (20 min). The reaction was quenched as described for the preparation of 14a from 12, and 14b (0.32 g) was obtained after the same workup. A solution of crude 14b (0.32 g) in THF/2 N HCl 4:1 (68 mL) was refluxed until TLC showed the disappearance of 14b (6 h). The reaction was worked up as described for the preparation of 15 from 14a, and CC purification yielded 15 (0.24 g, 0.76 mol, 87%) as a mixture of 15a and 15b (15a:15b, 82:18). Preparation of (+)-16 from 15. A solution of 15 (0.35 g; 1.1 mmol) and TsOH (0.19 g, 1.0 mmol) in toluene (54 mL) was heated at 85 °C until TLC showed the disappearance of 15 (48 h). After cooling to rt, the whole was diluted with AcOEt, washed with saturated NaHCO3 and brine, dried, and evaporated. The residue was purified by CC (AcOEt/n-hexane, 1:9) to give (+)-16 (0.22 g, 0.73 mmol, 66%): white powder, mp 165.1−166.8 °C; [α]25D +539.1 (c 2.7, CHCl3); IR (CHCl3) νmax 1728; 1H NMR (C6D6, 400.13 MHz) δ 5.10 (1H, d, J = 2.8 Hz), 3.53 (1H, d, J = 10.4 Hz), 3.15 (1H, d, J = 10.4 Hz), 2.51 (1H, bs), 2.06 (1H, d, J = 18.3 Hz), 1.95−1.76 (3H, m), 1.65 (3H, s), 1.61−1.53 (1H, m), 1.49−0.94 (10H, m), 0.91 (3H, s), 0.81 (1H, bs), 0.74 (1H, td, Jd = 3.9 Hz, Jt = 13.4 Hz), 0.64 (3H, s); 13 C NMR (C6D6, 100.61 MHz) δ 207.9, 131.5, 128.5 (CH), 64.8 (CH2), 55.5 (CH), 48.5 (CH), 48.0, 44.0 (CH2), 42.2 (CH), 38.74, 1948



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38.66, 35.5 (CH2), 32.6 (CH2), 32.2 (CH2), 27.5 (CH3), 26.3 (CH2), 22.3 (CH2), 21.7 (CH3), 18.5 (CH2), 18.1 (CH3); GC-MS m/z 302 [M]+ (24), 284 (14), 271 (16), 229 (14), 161 (14), 157 (11), 147 (26), 131 (28), 119 (52), 105 (100), 91 (79), 81 (56), 67 (43), 55 (59); HRESIMS m/z 325.2152 (calcd for C20H30O2 [M + Na]+, 325.2144). Preparation of (+)-17 from (+)-16. To a solution of (+)-16 (0.18 g, 0.60 mmol) in 1,2-ethanedithiol (1.1 mL, 13 mmol), cooled to 0 °C, was added BF3·Et2O (0.47 mL, 3.8 mmol) while stirring until TLC showed the disappearance of (+)-16 (10 min). The mixture was diluted with CH2Cl2 (30 mL), washed with 2 N NaOH (3 × 6 mL), H2O until neutral, and brine, dried, and evaporated. The mixture was purified by CC (AcOEt/n-hexane, 93:7) to give (+)-17 (191 mg, 0.50 mmol, 84%): white powder, mp 171.7−173.4 °C; [α]25D +105.9 (c 3.2, CHCl3); 1H NMR (CDCl3, 400.13 MHz) δ 5.11 (1H, pd, J = 2.0 Hz), 3.77 (1H, d, J = 10.8 Hz), 3.39 (1H, d, J = 10.8 Hz), 3.37−3.15 (4H, m), 2.47 (1H, d, J = 14.6 Hz), 2.33 (1H, d, J = 3.8 Hz), 2.13−2.05 (1H, m), 2.01 (1H, dd, J = 3.8 Hz, J = 11.6 Hz), 1.95 (1H, d, J = 14.6 Hz), 1.87−1.78 (4H, m), 1.73 (1H, d, J = 11.6 Hz), 1.71−1.28 (8H, m), 1.25−1.11 (2H, m), 0.97−0.85 (7H, m); 13C NMR (CDCl3, 100.61 MHz) δ 137.3, 126.8 (CH), 76.5, 65.4 (CH2), 56.2 (CH), 50.57, 50.47 (CH2), 49.5 (CH), 44.5 (CH), 40.1 (CH2), 39.3 (CH2), 38.65, 38.63, 35.4 (CH2), 32.6 (CH2), 31.3 (CH2), 30.2 (CH2), 27.1 (CH3), 24.5 (CH3), 22.0 (CH2), 18.2 (CH2), 17.8 (CH3); GC-MS m/ z 378 (14), 260 (16), 210 (8), 182 (11), 157 (11), 144 (22), 131 (21), 119 (32), 105 (100), 91 (41), 81 (24), 67 (20), 55 (32); HRESIMS m/z 401.1961 (calcd for C22H34OS2 [M + Na]+, 401.1949). Preparation of (+)-1 from (+)-17. A solution of (+)-17 (0.17 g, 0.44 mmol) in EtOH (58 mL) was stirred at 60 °C with Raney-Ni until TLC showed the disappearance of (+)-17 (30 min). The catalyst was removed by filtration through Celite, the solvent evaporated, and the mixture purified by CC (AcOEt/n-hexane, 5:95) to give (+)-1 (79 mg, 0.27 mmol, 62%): white solid, mp 116.1−117.6 °C; [α]25D +58.5 (c 1.8, CHCl3); 1H NMR (CDCl3, 400.13 MHz) δ 4.94 (1H, pd, J = 4.3 Hz), 3.80 (1H, d, J = 10.9 Hz), 3.41 (1H, dd, J = 1.0 Hz, J = 10.9 Hz), 2.19 (1H, t, J = 4.4 Hz), 2.01−1.93 (1H, m), 1.87−1.79 (1H, m), 1.75−1.10 (19H, m), 0.98−0.85 (7H, m); 13C NMR (CDCl3, 100.61 MHz) δ 138.9, 123.9 (CH), 65.5 (CH2), 51.1, 50.2 (CH), 44.4 (CH), 43.3 (CH), 38.8, 38.7, 35.6 (CH2), 33.4 (CH2), 32.4 (CH2), 32.0 (CH2), 31.8 (CH2), 30.0 (CH2), 27.2 (CH3), 22.12 (CH3), 22.09 (CH2), 18.4 (CH2), 17.9 (CH3); GC-MS m/z 288 [M]+ (20), 257 (54), 229 (8), 201 (8), 187 (20), 175 (15), 161 (33), 145 (33), 131 (59), 119 (43), 105 (100), 91 (78), 81 (72), 67 (47), 55 (77); HRESIMS m/z 311.2353 (calcd for C20H32O [M + Na]+, 311.2351). Preparation of (+)-2 from (+)-1. Acetic anhydride (0.22 mL, 2.1 mmol) was added to a solution of (+)-1 (33 mg, 0.11 mmol) in pyridine (1.3 mL). The solution was stirred until TLC showed the disappearance of (+)-1 (3 h). The mixture was diluted with CH2Cl2, washed with 0.1 N HCl, dried, evaporated, and purified by CC (Et2O/ n-hexane, 1:99) to give (+)-2 (38 mg, 0.11 mmol, 99%): white powder, mp 118.2−119.7 °C (lit. for (−)-2,2 96−97 °C); [α]25D +58.2 (c 1.2, CHCl3) [lit. for (−)-2,2 −17.02 (c 2.0, CHCl3)]; IR (CHCl3) νmax 1728; 1H NMR (CDCl3, 400.13 MHz) δ 4.94 (1H, pd, J = 3.2 Hz), 4.27 (1H, d, J = 10.5 Hz), 3.87 (1H, d, J = 10.5 Hz), 2.19 (1H, t, J = 4.3 Hz), 2.04 (3H, s), 2.02−1.94 (1H, m), 1.77−1.10 (19H, m), 1.00−0.90 (7H, m); 13C NMR (CDCl3, 100.61 MHz) δ 171.6, 138.9, 123.9 (CH), 67.2 (CH2), 51.1, 50.2 (CH), 44.3 (CH), 43.3 (CH), 38.8, 37.2, 36.3 (CH2), 33.4 (CH2), 32.2 (CH2), 31.9 (CH2), 31.8 (CH2), 29.9 (CH2), 27.7 (CH3), 22.12 (CH2), 22.11 (CH3), 21.2 (CH3), 18.4 (CH2), 17.9 (CH3); GC-MS m/z 330 [M]+ (20), 315 (15), 271 (13), 255 (41), 227 (24), 211 (9), 199 (13), 185 (17), 173 (19), 161 (24), 145 (41), 131 (59), 123 (28), 119 (45), 105 (100), 91 (83), 81 (72), 69 (23), 55 (68); HRESIMS m/z 353.2464 (calcd for C22H34O2 [M + Na]+, 353.2457).

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between (−)-2 and (+)-2, 1 and (+)-1 characterization data, crystallization solvents for all synthesized compounds. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; rinaldo. [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Preliminary experiments by R. Berrino and A. Marchetti and the experimental help of N. Demitri and the XRD-1 beamline staff at ELETTRA, Trieste (Italy), as well as financial support by Università degli Studi di Roma “La Sapienza” (Ateneo) are gratefully acknowledged. The authors are also grateful to Prof. A. Bianco for helpful discussions.

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REFERENCES

(1) Chamy, M. C.; Piovano, M.; Garbarino, J. A.; Miranda, C.; Gambaro, V. Phytochemistry 1990, 29, 2943−2946. (2) Garbarino, J. A.; Molinari, A. Phytochemistry 1990, 29, 3037− 3039. (3) Chamy, M. C.; Piovano, M.; Garbarino, J. A.; Gambaro, V. Phytochemistry 1991, 30, 3365−3368. (4) Atwal, K. S.; Marini Bettolo, R.; Sanchez, I. H.; Tsai, T. Y. R.; Wiesner, K. Can. J. Chem. 1978, 56, 1102−1113. (5) Tsai, T. Y. R.; Nambiar, K. P.; Krikorian, D.; Botta, M.; Marini Bettolo, R.; Wiesner, K. Can. J. Chem. 1979, 57, 2124−2134. (6) Sethi, S. P.; Atwal, K. S.; Marini Bettolo, R.; Tsai, T. Y. R. Can. J. Chem. 1980, 58, 1889−1891. (7) Bravetti, D.; Marini Bettolo, R.; Lupi, A. Helv. Chim. Acta 1982, 65, 371−376. (8) Marini Bettolo, R.; Tagliatesta, P.; Lupi, A.; Bravetti, D. Helv. Chim. Acta 1983, 66, 760−770. (9) Marini Bettolo, R.; Tagliatesta, P.; Lupi, A.; Bravetti, D. Helv. Chim. Acta 1983, 66, 1922−1928. (10) Lupi, A.; Patamia, M.; Grgurina, I.; Marini Bettolo, R.; Di Leo, O.; Gioia, P.; Antonaroli, S. Helv. Chim. Acta 1984, 67, 2261−2263. (11) Lupi, A.; Patamia, M.; Marini Bettolo, R. Helv. Chim. Acta 1988, 71, 872−875. (12) Berettoni, M.; Marini Bettolo, R.; Montanari, V.; Prencipe, T.; Romeo, S. Helv. Chim. Acta 1991, 74, 1671−1678. (13) Antonaroli, S.; Berettoni, M.; Cifarelli, G.; Lupi, A.; Marini Bettolo, R.; Romeo, S. Gazz. Chim. Ital. 1992, 122, 55−59. (14) Bartoletti, A.; Berettoni, M.; Catteruccia, F.; De Chiara, G.; Marini Bettolo, R.; Mastrangeli, C.; Scarpelli, R.; Tozzi, C.; Lamba, D. Gazz. Chim. Ital. 1996, 126, 223−226. (15) De Giacono, M.; Marini Bettolo, R.; Scarpelli, R. Tetrahedron Lett. 1997, 38, 3469−3470. (16) Marini Bettolo, R.; Migneco, L. M.; Moretti, P.; Scarpelli, R. J. Prakt. Chem. 1999, 341, 687−690. (17) Di Stefano, S.; Leonelli, F.; Garofalo, B.; Mandolini, L.; Marini Bettolo, R.; Migneco, L. M. Org. Lett. 2002, 4, 2783−2785. (18) Leonelli, F.; Borocci, S.; Migneco, L. M.; Marini Bettolo, R.; Lamba, D. Helv. Chim. Acta 2002, 85, 2817−2826. (19) Leonelli, F.; Caschera, B.; Silvestri, L.; Prastaro, A.; Corso, G.; Ceccacci, F.; La Bella, A.; Migneco, L. M.; Marini Bettolo, R. Helv. Chim. Acta 2008, 91, 598−607. (20) Leonelli, F.; Blesi, F.; Dirito, P.; Trombetta, A.; Ceccacci, F.; La Bella, A.; Migneco, L. M.; Marini Bettolo, R. J. Org. Chem. 2011, 76, 6871−6876. (21) Manchand, P. S.; Blount, J. F. J. Chem. Soc., Chem. Commun. 1975, 21, 894−895.

ASSOCIATED CONTENT

S Supporting Information *

1

H and 13C NMR spectra of all synthesized compounds, X-ray structure and crystallographic data for (+)-2, comparison 1949



Article

(22) Mohan, R. S.; Yee, N. K. N.; Coates, R. M.; Ren, Y.-Y.; Stamenkovic, P.; Mendez, I.; West, C. A. Arch. Biochem. Biophys. 1996, 330, 33−47. (23) Oikawa, H.; Toshima, H.; Ohashi, S.; König, W. A.; Kenmoku, H.; Sassa, T. Tetrahedron Lett. 2001, 42, 2329−2332. (24) Kodama, O.; Li, W. X.; Tamogami, S.; Akatsuka, T. Biosci., Biotechnol., Biochem. 1992, 56, 1002−1003. (25) Tamogami, S.; Mitani, M.; Kodama, O.; Akatsuka, T. Tetrahedron 1993, 49, 2025−2032. (26) Kodama, O.; Suzuki, T.; Miyakawa, J.; Akatsuka, T. Agric. Biol. Chem. 1988, 52, 2469−2473. (27) Bible, R. H., Jr.; Burtner, R. R. J. Org. Chem. 1961, 26, 1174− 1180. (28) Muzart, J. Synthesis 1993, 11−27. (29) De Santis, B.; Iamiceli, A. L.; Marini Bettolo, R.; Migneco, L. M.; Scarpelli, R.; Cerichelli, G.; Fabrizi, G.; Lamba, D. Helv. Chim. Acta 1998, 81, 2375−2387. (30) Unfortunately a direct comparison was not possible, as samples of 1 and (−)-2 were no longer available in Prof. Garbarino’s laboratory. The request for Calceolaria samples could also not be met (private communications to R.M.B.). (31) No specific rotation or melting point was reported for this compound. (32) Crystallographic data for the structure (+)-2 reported in this paper have been deposited with the Cambridge Crystallographic Data Centre (CCDC-871942). Copies of the data can be obtained, free of charge, on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-336033 or e-mail: [email protected]). (33) It should be noted that also the data recorded by Coates and coworkers22 do not fit those of the enantiomer isolated from Calceolaria latifolia,2 to which the nominal structure 6 was attributed.

1950


Regio- and Diastereoselective Synthesis and X-ray Structure

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