Stereoselective synthesis of highly substituted bicyclic γ-lactones using homoaldol addition of 1-(1-cycloalkenyl)methyl carbamates

PAPER

2303

Stereoselective Synthesis of Highly Substituted Bicyclic g-Lactones Using

Homoaldol Addition of 1-(1-Cycloalkenyl)methyl Carbamates

S

a

tereoselective

Synthe

u

sis of Highly

s

S

ubstitute

t

d

B

icy

a

clic

g

-Lact

f

one

s

a Özlügedik,^aJesper Kristensen,^bJenny Reuber,^aRoland Fröhlich,^a,1Dieter Hoppe*^a

b

Received 1 April 2004; revised 27 May 2004

Dedicated to Professor Wilhelm Flitsch on the occasion of his 80th birthday

O

Abstract: Stereoselective addition of aldehydes 4 to metallated 1-

(1-cycloalkenyl)methyl N,N-diisopropylcarbamates 1 gave cyclic

homoaldol adducts 6. By applying the (–)-sparteine method, enan-

H

O

OH

+

O

n

R²

tiomerically enriched products were obtained. These were oxida-

tively cyclized to diastereomerically pure g-lactones 8 via the g-

lactol ethers 7. After deprotonation of g-lactones 8 with lithium hex-

amethyldisilazide, a further substitution was achieved. By trapping

the lactone enolates 11 with b-naphthylmethyl bromide, single dia-

stereomers of g-lactones 12 were produced.

R¹

B

R¹

A

R²

C

M

O

1. Base

2. R³X

O

N

n

O

R³

R¹

Key words: asymmetric synthesis, 1-alkenyl carbamates, homoal-

dol addition, (–)-sparteine, bicyclic lactones

D

O

n

M = Li, Ti(Oi-Pr)₃

R¹= CH₃, H

n = 1–4

R¹

R²

E

A few enantiomerically enriched 1-heterosubstituted al-

lyllithium compounds are readily accessible by (–)-

sparteine-induced deprotonation of achiral precursors.^2,3

After lithium-titanium exchange, a chiral homoenolate is

produced, which adds stereoselectively to aldehydes and

ketones.

Scheme 1 Strategy for the synthesis of bicyclic g-lactones

deprotonation of 1 (Conditions B), the pro-S proton was

removed to form (S)-2·(–)-sparteine with selectivities ex-

ceeding 90:10.³However, with the exception of the con-

figurationally stable g-methyl-substituted derivatives 2b

and 2d, an epimerisation to form substantial amounts of

(R)-2·(–)-sparteine competes with the lithium-titanium

exchange, which proceeds stereospecifically with inver-

sion of configuration. Since the reaction of Ti(Oi-Pr)₄was

sluggish, we applied the more reactive ClTi(Oi-Pr)₃.⁵Al-

though the yields of adducts 6 were quite low,^7,8a reason-

able degree of chirality transfer was maintained (Table 1).

We recently published the generation of enantioenriched

(1-lithiomethyl)-1-cycloalkenylmethyl N,N-diisopropyl-

carbamates D and their asymmetric homoaldol reaction

with p-bromobenzaldehyde to serve as equivalents for ho-

moenolate synthons B (Scheme 1).⁴The application of

this methodology to the synthesis of bicyclic g-lactones A

from aldehydes C and their further elaboration to highly

substituted lactones of type E through introduction of a

further residue R³by means of enolate chemistry are re-

ported in this paper.

Methanolysis of 6 in the presence of catalytic mercuric

acetate provided the g-lactol ethers 7 as anomeric mix-

tures.⁹Grieco oxidation^9,10then furnished the bicyclic g-

lactones 8. Substrates with annulated five- and six-mem-

bered rings gave products as essentially pure diastereo-

mers (Table 2). Larger rings, such as cycloheptane and

cyclooctane gave rise to mixtures of cis- and trans-fused

bicycles (rac-8ei and rac-8fi, entries 13 and 14). The rel-

ative configuration could be unambiguously assigned due

to NOE effects in ¹H NMR between the bridgehead proton

and the CH₃group.

For the synthesis of the racemic adducts 6 (Scheme 2), the

deprotonation of (cycloalkenyl)methyl diisopropylcar-

bamates 1a–1f (Cb = diisopropylcarbamate) was carried

out by treatment with n-butyllithium–N,N,N¢,N¢-tetra-

methylethylenediamine (TMEDA) in toluene (Conditions

A). The intermediate lithium compound rac-2·TMEDA

was converted to the (triisopropoxy)titanium derivative

rac-3 with three equivalents of Ti(Oi-Pr)₄; aldehyde 4 was

then added.⁵According to the Zimmerman-Traxler transi-

tion state⁶TS5 the Z-anti-diastereomers rac-6 were

formed with diastereoselectivities greater then 95:5.

When n-butyllithium–(–)-sparteine was used for the

The vinyl carbamate 6df (82% ee), bearing a mercuric

salt-sensitive unsaturated side chain, required a more

elaborate strategy previously applied by us in the synthe-

sis of the pheromone (+)-eldanolide.¹¹Conversion of 6df

to the silyl ether 9, vinyl deprotonation and subsequent

quenching of the vinyllithium intermediate with dimeth-

yldisulfide, afforded the monothioacetal 10. Compound

10 was solvolized by aqueous MeOH–methanesulfonic

acid to yield in 56% lactone 8df with 82% ee (Scheme 3).

SYNTHESIS 2004, No. 14, pp 2303–2316

x

x.

x

.

2

0

4

Advanced online publication: 19.08.2004

DOI: 10.1055/s-2004-831170; Art ID: T03604SS

2304

M. Özlügedik et al.

PAPER

.

Li (−)-sparteine

Ti(OiPr)₃

OCb

H

a)

b)

OCb

n

R¹

2

1

3

c)

OMe

O

H

d)

Ti(OiPr)₃

OCb

OH

n

O

OCb

R²

R¹

R²

7

TS5

6

R²

Me

i-Pr

n-Pr

n-Oct

Ph

CH=CH₂

1-naphthyl

ferrocenyl

p-Br-C₆H₄

4

a

b

c

d

e

f

g

h

i

e)

1–3,5–8 R¹

n

a

b

c

d

e

f

H

Me

H

Me

1

2

3

4

O

H

O

n

R¹

R²

8

Scheme 2 Reagents and conditions: a) s-BuLi, TMEDA, toluene, –78 °C for racemates (Conditions A) or n-BuLi, (–)-sparteine, toluene,

–78 °C for enantioenriched products (Conditions B). b) Ti(OiPr)₄or ClTi(OiPr)₃, 3 equiv c) i. R²CHO (4), ii. 2 N HCl. d) Hg(OAc)₂(5–10

mol%), MeSO₃H (2 equiv) in MeOH. e) m-ClC₆H₄CO₃H–BF₃·OEt₂.

Table 1 Prepared Homoaldol Products

d

Entry

1

Substrates

1a + 4a

1a + 4b

1a + 4c

1a + 4d

1b + 4b

1b + 4e

1b + 4f

1b + 4i

1c + 4b

1c + 4e

1d + 4b

1d + 4c

Conditions

Ti-Reagent

Ti(Oi-Pr)₄

ClTi(Oi-Pr)₃

Ti(Oi-Pr)₄

ClTi(Oi-Pr)₃

Ti(Oi-Pr)₄

ClTi(Oi-Pr)₃

Product^a,b

rac-6aa

rac-6ab

rac-6ac

rac-6ad

6bb

Yield (%)

83

er^c

[a]_D

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

–

2

79

–

3

69

–

4

71

–

5

79

87:13

–

+29.6

–

6

rac-6bb

6be

77

7

70

86:14

–

+82.7

–

8

rac-6be

6bf

77

9

57

85:15

–

+70.1

–

10

11

12

13

14

15

16

17

18

19

rac-6bf

6bi^f

59

29

96:4

–

+113

–

rac-6bi

6cb

79

70

77:23

–

+18.1

–

rac-6cb

6ce

68

82

76:24

–

–36.2

–

rac-6ce

6db

88

40

94:6

–

+48.1

–

rac-6db

6dc

80

25

89:11

+61.7

Synthesis 2004, No. 14, 2303–2316 © Thieme Stuttgart · New York

PAPER

Stereoselective Synthesis of Highly Substituted Bicyclic g-Lactones

2305

Table 1 Prepared Homoaldol Products (continued)

d

Entry

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

Substrates

1d + 4c

1d + 4d

1d + 4e

1d + 4f

1d + 4g

1d + 4h

1d + 4i

1e + 4i

1f + 4i

Conditions

Ti-Reagent

Ti(Oi-Pr)₄

Product^a,b

rac-6dc

6dd

Yield (%)

83

er^c

–

[a]_D

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

–

e

ClTi(Oi-Pr)₃

Ti(Oi-Pr)₄

41

–

+45.4

–

rac-6dd

6de

66

–

ClTi(Oi-Pr)₃

Ti(Oi-Pr)₄

34

96:4

–

–34.3

–

rac-6de

6df

85

ClTi(Oi-Pr)₃

Ti(Oi-Pr)₄

34

91:9

–

+30.4

–

rac-6df

6dg

57

ClTi(Oi-Pr)₃

Ti(Oi-Pr)₄

33

88:12

–

+6.8

–

rac-6dg

6dh

48

e

ClTi(Oi-Pr)₃

Ti(Oi-Pr)₄

27

–

+166

–

rac-6dh

6di^f

65

–

ClTi(Oi-Pr)₃

Ti(Oi-Pr)₄

35

94:6

–

–46.3

–

rac-6di^f

6ei^f

76

ClTi(Oi-Pr)₃

Ti(Oi-Pr)₄

22

75:25

–

+34.4

–

rac-6ei

6fi^f

71

ClTi(Oi-Pr)₃

Ti(Oi-Pr)₄

21

69:31

–

+6,8

–

1f + 4i

rac-6fi

72

^aFor R¹, R², R³, and n, see Scheme 2.

^bIn all cases, no second diastereomer was found by ¹H NMR. Thus, the diastereomeric ratios are assumed to be >95:5.

^cDetermined by ¹H NMR shift experiment or by chiral GC.

^dc = 0.19–0.52 in CHCl₃.

^eNot determined.

^fThese compounds have already been reported in the literature.⁴

Table 2 Prepared Lactones 8

Table 2 Prepared Lactones 8 (continued)

d

Product^a

Yield

(%)

er^b,c

[a]_D

Entry Starting

material^a

Product^a

Yield

(%)

er^b,c

[a]_D

d

Entry Starting

material^a

1

2

rac-6aa

rac-6ab

rac-6ac

rac-6ad

6bb

rac-8aa

rac-8ab

rac-8ac

rac-8ad

8bb

45

73^e

71

83

54

56

49

75

78

56

80

73

–

13

14

rac-6ei

rac-6fi

rac-8ei

rac-8fi

67

62

–

^aFor R¹, R², R³, and n, see Scheme 2.

3

–

^bThe ee value of the starting enol carbamate 8 is given, since a race-

misation is not possible.

4

–

^cDiastereomeric ratios of rac-8ei and rac-8fi are 66:34 and 75:25, re-

spectively. In all other cases, no second diastereomer was found by ¹H

NMR. Thus, the diastereomeric ratios are assumed to be >95:5.

^dc = 0.10–1.34 in CHCl₃.

5

87:13

90:10

96:4

–

+21.3

–6.2

6

6be

8be

^eCrude.

7

6bi

8bi

–3.0

^fNot determined.

8

rac-6dc

6dd

rac-8dc

8dd

–

f

The lactones 8bi and 8di, containing bromine as a heavy

atom, were crystalline. These were subjected to X-ray

crystal structure analysis with anomalous diffraction

(Figures 1 and 2) in order to elucidate their absolute con-

figurations. These structures correlated well with those

predicted and therefore confirm the proposed configura-

tions of the intermediates and related derivatives reported

in this paper.

9

–

+25.4

+33.6

–85.5

–15.8

10

11

12

6df

8df

91:9

88:12

94:6

6dg

8dg

6di

8di

Synthesis 2004, No. 14, 2303–2316 © Thieme Stuttgart · New York

2306

M. Özlügedik et al.

PAPER

In order to demonstrate the further synthetic diversity of-

fered by the bicyclic lactones 8, we investigated the prep-

aration and alkylation of a selection of examples

(Scheme 4, Table 3). Lactones rac-8 were converted with

lithium hexamethyldisilazide (LiHMDS) into the lactone-

enolates 11 and alkylated by treatment with 2-(bromo-

methyl)naphthalene to furnish the unpolar products 12a–f

as single diastereomers. Exemplary, a ¹H NMR investiga-

tion of compound 12f revealed the cis-configuration by an

NOE effect between the 3a-CH₃and the 7a-CH₂groups.

As predicted, the bicyclic enolate 11 is attacked exclu-

sively from the convex face.¹³

b)

a)

OCb

6df

OSiMe₃

9

SCH₃

O

H

c)

OCb

O

OSiMe₃

8df

10

Scheme 3 Reagents and conditions: a) ClSiMe₃, Et₃N, CH₂Cl_2,0 °C

→ r.t., 15 h. b) i. n-BuLi. ii. MeSSMe, THF, 3 h, –78 °C. c) MeSO₃H,

MeOH, 15 h, 50 °C.

In conclusion, the asymmetric deprotonation of achiral 2-

substituted (1-cycloalkenyl)methyl carbamates, with sub-

sequent homoaldol reaction and enolate alkylation pro-

vides a versatile brick-box system for the synthesis of

highly substituted bicyclic lactones. Some examples for

more complex elaboration will be found in ref.¹⁴

O

OLi

O

H

a)

O

n

R¹

R²

8

11

b)

O

n

12

R¹

R²

Scheme 4 Reagents and conditions: a) LiHMDS, THF, 1 h, –78 °C.

b) 2-(bromomethyl)naphthalene, THF, –78 °C → r.t., 15 h.

Figure 1 Structure of 8bi¹²

Table 3 Prepared g-Lactones 12

Entry Starting

material

Product

n

R¹

R²

Yield

(%)

1

2

3

4

5

6

rac-8aa

rac-8ab

rac-8ac

rac-8ad

rac-8ae

rac-8bc

rac-12a

rac-12b

rac-12c

rac-12d

rac-12e

rac-12f

1

2

H

Me

45

42

46

48

46

52

H

i-Pr

n-Pr

n-Oct

Ph

H

Me

n-Pr

n-BuLi (1.6 M in hexane) and s-BuLi [1.4 M in hexane–cyclohex-

ane (92:8)] were used. Aldehydes were distilled prior to use. (–)-

Sparteine was kept under Ar in a refrigerator after the original bot-

tles had been opened. All reactions, which are sensitive to moisture

or air, were carried out under Ar using the septum-and-syringe tech-

niques. All solvents were purified by distillation or dried (toluene,

Et₂O ether) prior to use. Flash chromatography was carried out with

silica gel (40–63 mm) using an Ar pressure of 1.2–1.4 bar. Chiral GC

was carried out with a Beta-Dex^TM120 capillary column, 30 m, Su-

pelco. ¹H and ¹³C NMR spectra were recorded on ARX 300, Bruker.

Figure 2 Structure of 8di¹²

Synthesis 2004, No. 14, 2303–2316 © Thieme Stuttgart · New York

PAPER

Stereoselective Synthesis of Highly Substituted Bicyclic g-Lactones

2307

Chemical shifts in brackets refer to the minor isomer caused by E/

Z-isomerism in the OCS group. CDCl₃was used as solvent, chemi-

cal shifts are reported in ppm (d); ¹H shifts are related to TMS and

¹³C shifts to d_c= 77.0. Y indicates pseudo multiplicities. IR absorp-

tion spectra were recorded using a Perkin-Elmer 298 and a FT-IR

5DXC (Nicolet, Offenbach a. M.). Mass spectrocopy was per-

formed using a MAT 8200 (Finnigan, Bremen) or a Quattro LC-Z

(Micromass).

2 H), 2.19–2.23 (m, 2 H), 2.87–2.95 (m, 1 H), 3.13 (dt, J = 2.4, 9.9

Hz, 1 H), 3.89 (m_c, 2 H), 7.02 (m_c, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 14.3 (CH₃), 20.7 (CH₃), 24.3

(CH₂), 28.8 (CH₂), 28.9 (CH₂), 29.9 (CH), 43.8 (CH), 46.2 (CH),

77.5 (CH), 126.8 (C_q), 130.4 (CH), 152.4 (C=O).

Anal. Calcd for C₁₇H₃₁NO₃(297.43): C, 68.65; H, 10.51; N, 4.71.

Found: C, 68.61; H, 10.63; N, 4.73.

rac-{1Z,1[2RS,2(1SR)]}-1-[2-(1-Hydroxybutyl)cyclopentyl-

idene]methyl N,N-Diisopropylcarbamate (rac-6ac)

Homoaldol Reaction of Allyl Carbamates 1; General Procedure

(GP1)

According to GP1, allyl carbamate 1a (1.13 g, 5.00 mmol) and

TMEDA (640 mg, 5.50 mmol) were dissolved in toluene (15 mL)

and cooled to –78 °C before 1.2 M s-BuLi (4.6 mL, 5.50 mmol) was

added. The reaction mixture was stirred for 30 min after which TiPT

(4.27 g, 15.0 mmol) was added. The orange-coloured solution was

stirred for 1 h at –78 °C then butanal (4c, 450 mg, 6.25 mmol), dis-

solved in toluene (1.0 mL), was added. After workup, and flash

chromatography (petroleum ether–EtOAc, 4:1) 6ac (1.28 g, 69%)

was obtained as a colourless oil; R_f0.39 (petroleum ether–EtOAc,

4:1).

To a solution of allyl carbamate 1 (1.0 mmol) and diamine (1.1–1.2

mmol) in toluene (3–10 mL) at –78 °C was added dropwise n-BuLi

(1.6 M in hexane) or s-BuLi (0.97–1.20 M in hexane) (1.1–1.2

mmol) under vigorous stirring. The reaction mixture was stirred at

this temperature for 10–120 min and then a precooled (–78 °C) so-

lution of tetraisopropoxytitanium (TiPT) or chlorotriisopropoxyti-

tanium (Cl-TiPT) (1 M in hexane, 1.1–3.6 mmol) was added. The

reaction mixture was stirred for 1 h at –78 °C and then, the aldehyde

(1.5–3.0 mmol), dissolved in toluene (1 mL), was added. Finally,

the reaction mixture was stirred for 1 h at –78 °C before it was al-

lowed to warm to r.t. The solution was poured into ice-cooled mix-

ture of Et₂O (15 mL) and aq 2 N HCl (15 mL). The aqueous layer

was extracted with Et₂O (3 × 15 mL). The combined organic ex-

tracts were dried over anhyd MgSO₄and concentrated in vacuo. The

residue was purified by silica gel flash column chromatography.

IR (film): 3491 (OH), 1703 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.90 (t, J = 6.9 Hz, 3 H), 1.23

[1.23] (d, J = 6.9 Hz, 12 H), 1.28–1.86 (m, 8 H), 2.11–2.35 (m, 2 H),

2.80–2.90 (m, 1 H), 3.75 (dt, J = 2.5, 8.0 Hz, 1 H), 3.91 (sept, J =

6.9 Hz, 2 H), 7.02 (m_c, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 14.2 (CH₃), 19.0 (CH₂), 20.8

(CH₃), 24.7(CH₂), 28.3(CH₂), 29.5 (CH₂), 36.3 (CH₂), 46.3 (CH),

46.5 (CH), 73.3 (CH), 126.4 (C_q), 130.3 (CH), 152.7 (C=O).

rac-{1Z,1[2RS,2(1SR)]}-1-[2-(1-Hydroxyethyl)cyclopentyl-

idene]methyl N,N-Diisopropylcarbamate (rac-6aa)

According to GP1, allyl carbamate 1a (1.13 g, 5.00 mmol) and

TMEDA (640 mg, 5.50 mmol) were dissolved in toluene (15 mL)

and cooled to –78 °C before 1.2 M s-BuLi (4.6 mL, 5.50 mmol) was

added. The reaction mixture was stirred for 30 min after which TiPT

(4.27 g, 15.0 mmol) was added. The orange-coloured solution was

stirred for 1 h at –78 °C and then ethanal (4a, 275 mg, 6.25 mmol),

dissolved in toluene (1.0 mL) was added. After workup, the residue

was purified by flash chromatography (petroleum ether–Et₂O, 2:1)

to give rac-6aa (1.12 g, 83%) as a colourless oil; R_f0.40 (petroleum

ether–Et₂O, 2:1).

Anal. Calcd for C₁₇H₃₁NO₃(297.43): C, 68.65; H, 10.51; N, 4.71.

Found: C, 68.53; H, 10.54; N, 5.03.

rac-{1Z,1[2RS,2(1SR)]}-1-[2-(1-Hydroxynonyl)cyclopentyl-

idene]methyl N,N-Diisopropylcarbamate (rac-6ad)

According to GP1, allyl carbamate 1a (1.35 g, 6.0 mmol) and TME-

DA (698 mg, 6.60 mmol) were dissolved in toluene (15.00 mL) and

cooled to –78 °C before 0.97 M s-BuLi (6.8 mL, 6.60 mmol) was

added. The reaction mixture was stirred for 30 min after which TiPT

(4.27 g, 15.0 mmol) was added. The orange-coloured solution was

stirred for 1 h at –78 °C then n-nonanal (4d, 1.12 g, 7.50 mmol), dis-

solved in toluene (1.0 mL), was added. After workup and flash chro-

matography (petroleum ether–Et₂O, 2:1) rac-6ad (1.57 g, 71%) was

obtained as a colourless oil; R_f0.47 (petroleum ether–Et₂O, 2:1).

IR (film): 3461 (OH), 1701 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.13 (d, J = 6.3 Hz, 3 H), 1.23

[1.22] (d, J = 6.8 Hz, 12 H), 1.40–1.96 (m, 4 H), 2.14–2.34 (m, 2 H),

2.85–2.96 (m, 1 H), 3.75 (dq, J = 6.3, 7.7 Hz, 1 H), 3.91 (m, 2 H),

7.01 (m_c, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 20.0 (CH₃), 20.8 (CH₃), 24.7

(CH₂), 28.0 (CH₂), 29.4 (CH₂), 46.3 (CH), 47.8 (CH), 69.7 (CH),

126.4 (C_q), 130.4 (CH), 152.7 (C=O).

IR (film): 3489 (OH), 1706 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.84 (t, J = 6.8 Hz, 3 H), 1.22

[1.22] (d, J = 6.8 Hz, 12 H), 1.12–1.84 (2 × m, 18 H), 2.13–2.33 (m,

2 H), 2.85–2.95 (m, 1 H), 3.54 (m_c, 1 H), 3.90 (m_c, 2 H), 7.01 (m_c,

1 H).

¹³C NMR (75 MHz, CDCl₃): d = 14.0 (CH₃), 20.8 (CH₃), 22.6

(CH₂), 24.7 (CH₂), 25.8 (CH₂), 28.3 (CH₂), 29.2 (CH₂), 29.4 (CH₂),

29.6 (CH₂), 29.8 (CH₂), 31.9 (CH₂), 34.0 (CH₂), 46.3 (CH), 46.4

(CH), 73.5 (CH), 126.4 (C_q), 130.3 (CH), 152.7 (C=O).

Anal. Calcd for C₁₅H₂₇NO₃(269.38): C, 66.88; H, 10.10; N, 5.20.

Found: C, 66.70; H, 9.88; N, 5.33.

rac-{1Z,1[2RS,2(1SR)]}-1-[2-(1-Hydroxy-2-methylpropyl)cy-

clopentylidene]methyl N,N-Diisopropylcarbamate (rac-6ab)

According to GP1, allyl carbamate 1a (225 mg, 1.00 mmol) and

TMEDA (128 mg, 1.10 mmol) were dissolved in toluene (3 mL)

and cooled to –78 °C before 1.30 M sec-BuLi (0.85 mL, 1.10 mmol)

was added. The reaction mixture was stirred for 30 min after which

TiPT (835 mg, 3.00 mmol) was added. The orange-coloured solu-

tion was stirred for 1 h at –78 °C then 2-methylpropanal (4b, 90 mg,

1.25 mmol), dissolved in toluene (0.5 mL), was added. After work-

up and flash chromatography (petroleum ether–Et₂O, 2:1) rac-6ab

(236 mg (79%)) was obtained as a colourless oil; R_f0.19 (petroleum

ether–Et₂O, 4:1).

Anal. Calcd for C₂₂H₄₁NO₃(367.57): C, 71.89; H, 11.24; N, 3.81.

Found: C, 72.00; H, 11.53; N, 4.13.

{1Z,1[2S,2(1R)]}-1-[2-(1-Hydroxy-2-methylpropyl)-2-methyl-

cyclopentylidene]methyl N,N-Diisopropylcarbamate (6bb)

According to GP1, allyl carbamate 1b (239 mg, 1.00 mmol) and

(–)-sparteine (281 mg, 1.20 mmol) were dissolved in toluene (5.00

mL) and cooled to –78 °C before 1.6 M n-BuLi (0.75 mL, 1.20

mmol) was added. The reaction mixture was stirred for 30 min be-

fore TiPT (853 mg, 3.00 mmol) was added. The orange-coloured

solution was stirred for 1 h at –78 °C and then 2-methylpropanal

(4b, 144 mg, 2.00 mmol), dissolved in toluene (1.00 mL), was add-

IR (film): 3499 (OH), 1705 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.85, 0.97 (d, J = 6.9 Hz, 6 H),

1.20 (m_c, 12 H), 1.33–1.57 (m, 2 H), 1.70–1.74 (m, 2 H), 1.88 (m_c,

Synthesis 2004, No. 14, 2303–2316 © Thieme Stuttgart · New York

2308

M. Özlügedik et al.

PAPER

ed. After workup, the residue was purified by flash chromatography

(petroleum ether–Et₂O, 4:1) to give 6bb (247 mg, 79%) as a colour-

less solid; R_f0.39 (petroleum ether–EtOAc, 4:1); mp 56 °C (petro-

leum ether–EtOAc); [a]_D²⁰= +29.6 (c = 0.26, CHCl₃); 73% ee.¹⁵

¹H NMR (300 MHz, CDCl₃): d = 1.16–1.28 (m, 12 H), 1.30 (s, 3 H),

1.33–1.84 (m, 4 H), 2.20 (dddd, J = 2.4, 7.4, 9.8, 15.1 Hz, 1 H), 2.34

(ddddd, J =1.4, 1.4, 4.1, 8.4,13.7 Hz, 1 H), 3.40–4.25 (br s, 2 H),

4.41 (m_c, 1 H), 5.14 (ddd, J = 1.7, 1.7, 10.6 Hz, 1 H), 5.24 (ddd, J =

17.2, 1.7, 1.7 Hz, 1 H), 5.93 (ddd, J = 5.0, 10.6, 17.3 Hz, 1 H), 6.91

(dd, J = 1.6, 2.3 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 20.7 (CH₃), 22.6 (CH₃), 24.0

(CH₂), 32.0 (CH₂), 36.1 (CH₂), 46.3 (CH), 49.6 (C_q), 77.1 (CH),

115.3 (CH₂), 129.2 (CH), 129.9 (C_q), 138.3 (CH), 151.9 (C=O).

IR (KBr): 3493 (OH), 1695 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.93 (d, J = 6.7 Hz, 3 H), 0.94 (d,

J = 6.9 Hz, 3 H), 1.14–1.32 (m, 12 H), 1.28 (s, 3 H), 1.37–2.00 (2 ×

m, 5 H), 2.27–2.22 (m, 2 H), 3.39–4.41 (br s, 2 H), 3.67 (br s, 1 H),

6.89 (dd, J = 1.6, 2.2 Hz, 1 H).

Anal. Calcd for C₁₇H₂₉NO₃(295.42): C, 69.12; H, 9.89; N, 4.74.

Found: C, 69.03; H, 9.83; N, 4.65.

¹³C NMR (75 MHz, CDCl₃): d = 17.5 (CH₃), 20.7 (CH₃), 23.1

(CH₃), 24.4 (CH₃), 23.9 (CH₂), 30.1 (CH), 32.2 (CH₂), 36.7 (CH₂),

46.3 (CH), 50.6 (C_q), 80.7 (CH), 128.9 (CH), 130.8 (C_q), 151.8

(C=O).

Carbamate rac-6bf was prepared by applying the analogous proce-

dure with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1b (239

mg, 1.00 mmol) gave rac-6bf (174 mg, 59%).

Anal. Calcd for C₁₈H₃₃NO₃(311.46): C, 69.41; H, 10.68; N, 4.50.

Found: C, 69.46; H, 10.67; N, 4.22.

{1Z,1[2S,2(1R)]}-1-[2-(1-Hydroxy-2-methylpropyl)cyclohexyl-

idene]methyl N,N-Diisopropylcarbamate (6cb)

Carbamate rac-6bb was prepared by applying the analogous proce-

dure with sec-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1b (239

mg, 1.00 mmol) gave rac-6bb (240 mg, 77%).

According to GP1, allyl carbamate 1c (144 mg, 0.60 mmol) and

(–)-sparteine (155 mg, 0.66 mmol) were dissolved in toluene (3 mL)

and cooled to –78 °C before 1.6 M n-BuLi (0.41 mL, 0.66 mmol)

was added. The reaction mixture was stirred for 1 h after which

TiPT (0.53 mL, 1.80 mmol) was added. The orange-coloured solu-

tion was stirred for 1 h at –78 °C and then 2-methylpropanal (4b,

0.11 mL, 1.20 mmol), dissolved in toluene (1 mL), was added. After

workup, the residue was purified by flash chromatography (petro-

leum ether–Et₂O, 2:1) to give 6cb (132 mg, 70%) as a colourless oil;

R_f0.62 (petroleum ether–Et₂O, 3:1); [a]_D²⁰= +18.1, 53% ee.

¹H NMR (300 MHz, CDCl₃): d = 0.87 (d, J = 6.7 Hz, 3 H), 1.06 (d,

J = 6.7 Hz, 3 H), 1.24 (d, J = 6.7 Hz, 12 H), 1.35–1.60 (m, 4 H),

1.65–1.95 (m, 3 H), 2.00–2.20 (m, 3 H), 2.85–3.00 (m, 1 H), 3.73

(dd, J = 2.1, 10.5 Hz, 1 H), 3.70–4.20 (m, 2 H), 6.98 (d, J = 1.6 Hz,

1 H).

{1Z,1[2S,2(1R)]}-1-[2-(1-Hydroxy-1-phenylmethyl)-2-methyl-

cyclopentylidene]methyl N,N-Diisopropylcarbamate (6be)

According to GP1, allyl carbamate 1b (160 mg, 0.67 mmol) and

(–)-sparteine (188 mg, 0.80 mmol) were dissolved in toluene (5 mL)

and cooled to –78 °C before 1.6 M n-BuLi (0.50 mL, 0.80 mmol)

was added. The reaction mixture was stirred for 30 min after which

TiPT (682 mg, 2.40 mmol) was added. The orange-coloured solu-

tion was stirred for 1 h at –78 °C and then benzaldehyde (4e, 144

mg, 1.01 mmol), dissolved in toluene (1 mL), was added. After

workup, the residue was purified by flash chromatography (petro-

leum ether–Et₂O, 10:1) to give 6be (162 mg, 70%) as a colourless

oil; R_f0.16 (petroleum ether–Et₂O, 10:1); [a]_D²⁰= +82.7 (c = 0.52,

CHCl₃), 72% optical purity.

¹³C NMR (75 MHz, CDCl₃): d = 13.4 (CH₃), 19.5 (CH₃), 20.7

(CH₂), 26.7 (CH₂), 27.4 (CH₂), 27.6 (CH₂), 28.8 (CH), 38.1 (CH),

46.0 (CH), 72.2 (CH), 123.0 (C_q), 131.3 (CH), 153.1 (C=O).

IR (film): 3483 (OH), 1686 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.22–1.54 (m, 2 H), 1.31 (d, J =

6.4 Hz, 12 H), 1.41 (s, 3 H), 1.77–2.01 (m, 2 H), 2.13–2.30 (m, 2 H),

3.75 [4.19] (br s, 2 H), 5.00 (s, 1 H), 6.97 (dd, J = 1.7 H, 2.2 Hz, 1

H), 7.19–7.40 (m, 5 H).

Anal. Calcd for C₁₈H₃₃NO₃(311.46): C, 69.41; H, 10.68; N, 4.50.

Found: C. 69.45: H. 10.80: N. 4.51.

Carbamate rac-6cb was prepared applying the analogous procedure

with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1c (1.093 g,

4.57 mmol) gave rac-6cb (0.966 g, 68%).

¹³C NMR (75 MHz, CDCl₃): d = 20.8 (CH₃), 22.7 (CH₃), 23.7

(CH₂), 31.7 (CH₂), 36.3 (CH₂), 50.7 (C_q), 46.4 (CH), 77.7 (CH),

127.1 (CH), 127.5 (CH), 127.5 (CH), 129.5 (CH), 130.5 (C_q), 141.7

(C_q), 151.9 (C=O).

{1Z,1[2S,2(1R)]}-1-[2-(1-Hydroxymethyl-1-phenyl)cyclohexyl-

idene]methyl N,N-Diisopropylcarbamate (6ce)

Anal. Calcd for C₂₁H₃₁NO₃(345.48): C, 73.01; H, 9.04; N, 4.05.

Found: C, 73.10; H, 9.28; N, 3.85.

According to GP1, allyl carbamate 1c (165 mg, 0.60 mmol) and

(–)-sparteine (155 mg, 0.66 mmol) were dissolved in toluene (3 mL)

and cooled to –78 °C before 1.6 M n-BuLi (0.41 mL, 0.66 mmol)

was added. The reaction mixture was stirred for 1 h after which

TiPT (0.53 mL, 1.80 mmol) was added. The orange-coloured solu-

tion was stirred for 1 h at –78 °C and then benzaldehyde (4e, 0.11

mL, 1.20 mmol), dissolved in toluene (1 mL), was added. After

workup, the residue was purified by flash chromatography (petro-

leum ether–Et₂O, 2:1) to give 6ce (196 mg, 82%) as a colourless oil;

Carbamate rac-6be was prepared by applying the analogous proce-

dure with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1b (287

mg, 1.20 mmol) gave rac-6be (319 mg, 77%).

{1Z,1[2S,2(1R)]}-1-[2-(1-Hydroxy-2-propenyl)-2-methylcyclo-

pentylidene]methyl N,N-Diisopropylcarbamate (6bf)

According to GP1, allyl carbamate 1b (1.00 g, 4.18 mmol) and (–)-

sparteine (1.18 g, 5.00 mmol) were dissolved in toluene (20 mL)

and cooled to –78 °C before 1.6 M n-BuLi (3.10 mL, 5.00 mmol)

was added. The reaction mixture was stirred for 30 min after which

TiPT (4.28 g, 15.0 mmol) was added. The orange-coloured solution

was stirred for 30 min at –78 °C and then 2-propenal (4f, 351 mg,

6.27 mmol), dissolved in toluene (1 mL), was added. After workup,

the residue was purified by flash chromatography (petroleum ether–

Et₂O, 6:1) to give 6bf (683 mg, 57%) as a colourless oil; R_f0.23 (pe-

troleum ether–EtOAc, 6:1); [a]_D²⁰= +70.1 (c = 0.37, CHCl₃). GC:

Supelco b-Dex^©120 (70% ee); the major enantiomer appears at

lower retention time.

20

R_f0.39 (petroleum ether–Et₂O, 2:1); [a]_D= –36.2; 52% ee; mp

92–94 ºC (petroleum ether–Et₂O).

¹H NMR (300 MHz, CDCl₃): d = 1.10–1.47 (m, 15 H), 1.47–1.70

(m, 1 H), 2.15–2.35 (m, 3 H), 2.85–2.95 (m, 1 H), 3.06–3.13 (m, 1

H), 3.8–4.2 (m, 2 H), 4.50 (d, J = 7.7 Hz, 1 H), 4.81 (d, J = 10.5 Hz,

1 H), 7.12 (d, J = 1.7 Hz, 1 H), 7.25–7.42 (m, 5 H).

¹³C NMR (75 MHz, CDCl₃): d = 21.4 (CH₃), 21.6 (CH₂), 26.8

(CH₂), 27.4 (CH₂), 27.7 (CH₂), 43.2 (CH), 44.5 (CH), 72.8 (CH),

122.0 (C_q), 126.9 (CH), 127.6 (CH), 128.2 (CH), 132.4 (CH), 142.9

(C_q), 153.2 (C=O).

IR (film): 3480 (OH), 1700 (C=O) cm^–1.

Synthesis 2004, No. 14, 2303–2316 © Thieme Stuttgart · New York

PAPER

Stereoselective Synthesis of Highly Substituted Bicyclic g-Lactones

2309

Anal. Calcd for C₂₁H₃₁NO₃(345.48): C, 73.01; H, 9.04; N, 4.05.

Found: C, 72.87; H, 9.39; N, 4.12.

{1Z,1[2S,2(1R)]}-1-[2-(1-Hydroxyoctyl)-2-methylcyclohexyl-

idene]methyl N,N-Diisopropylcarbamate (6dd)

According to GP1, allyl carbamate 1d (329 mg, 1.30 mmol) and

(–)-sparteine (366 mg, 1.56 mmol) were dissolved in toluene (5 mL)

and cooled to –78 °C before 1.6 M n-BuLi (0.98 mL, 1.56 mmol)

was added. The reaction mixture was stirred for 1 h after which 1.0

M Cl-TiPT solution in toluene (4.7 mL, 4.7 mmol) was added. The

dark solution was stirred for 1 h at –78 °C and then n-nonanal (4d,

277 mg, 1.95 mmol), dissolved in toluene (1 mL), was added. After

workup, the residue was purified by flash chromatography (petro-

leum ether–Et₂O, 4:1) to give 6dd (213 mg, 41%) as a colourless

oil; R_f0.32 (petroleum ether–Et₂O, 4:1); [a]_D²⁰= +45.4 (c = 0.52,

CHCl₃).

Carbamate rac-6ce was prepared by applying the analogous proce-

dure with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1c (244

mg, 1.02 mmol) gave rac-6ce (307 mg, 76%).

{1Z,1[2S,2(1R)]}-1-[2-(1-Hydroxy-2-methylpropyl)-2-methyl-

cyclohexylidene]methyl N,N-Diisopropylcarbamate (6db)

According to GP1, allyl carbamate 1d (116 mg, 0.46 mmol) and

(–)-sparteine (129 mg, 0.55 mmol) were dissolved in toluene (2 mL)

and cooled to –78 °C before 1.6 M n-BuLi (0.97 mL, 1.55 mmol)

was added. The reaction mixture was stirred for 1 h after which 1.0

M Cl-TiPT solution in toluene (1.6 mL, 1.65 mmol) was added. The

dark solution was stirred for 1 h at –78 °C and then 2-methylpropa-

nal (4b, 33 mg, 0.46 mmol), dissolved in toluene (0.5 mL), was add-

ed. After workup, the residue was purified by flash chromatography

(petroleum ether–Et₂O, 4:1) to give 6dc (60 mg, 40%) as a thick co-

lourless oil. Crystallisation from petroleum ether–Et₂O gave colour-

IR (film): 3497 (OH), 1716 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.86 (t, J = 7.0 Hz, 3 H), 1.01–1.79

(m, 32 H), 1.19 (s, 3 H), 1.97–2.23 (m, 2 H), 3.58 [4.17] (br s, 2 H),

3.86 (dd, J = 2.2, 9.1 Hz, 1 H), 6.89 (d, J = 1.4 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 14.1 (CH₃), 20.7 (CH₃), 21.2

(CH₃), 21.2 (CH₂), 22.6 (CH₂), 26.8 (CH₂), 26.8 (CH₂), 27.4 (CH₂),

29.0 (CH₂), 29.3 (CH₂), 29.7 (CH₂), 29.8 (CH₂), 31.9 (CH₂), 36.5

(CH₂), 44.0 (C_q), 45.6 [46.8] (CH), 72.7 (CH), 124.5 (C_q), 132.1

(CH), 152.3 (C=O).

20

less crystals; R_f0.44 (petroleum ether–Et₂O, 4:1); [a]_D= +48.1

(88% op); mp 53–54 °C.

¹H NMR (300 MHz, CDCl₃): d = 0.97 (d, J = 6.7 Hz, 3 H), 1.04 (d,

J = 6.7 Hz, 3 H), 1.15–1.44 (m, 17 H), 1.48–1.57 (m, 2 H), 1.67–

1.80 (m, 3 H), 1.92 (septd, J = 2.9, 6.7 Hz, 1 H), 2.00–2.08 (m, 1 H),

2.14–2.26 (m, 1 H), 3.74 (d, J = 2.9 Hz, 1 H), 3.50–4.30 (m, 2 H),

6.87 (d, J = 1.7 Hz, 1 H).

Anal. Calcd for C₂₄H₄₅NO₃(395.62): C, 72.86; H, 11.46; N, 3.54.

Found: C, 73.17; H, 11.55; N, 3.52.

¹³C NMR (75 MHz, CDCl₃): d = 18.0 (CH₃), 21.0 (CH₃), 21.6

(CH₃), 22.7 (CH₂), 24.2 (CH₂), 26.8 (CH₂), 28.3 (CH₂), 29.4 (CH),

36.9 (CH), 45.2 (CH), 77.8 (CH), 125.8 (C_q), 132.2 (CH), 156.6

(C=O).

Carbamate rac-6dd was prepared by applying the analogous proce-

dure with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1d (228

mg, 0.90 mmol) gave rac-6dd (253 mg, 66%).

{1Z,1[2S,2(1R)]}-1-[2-(1-Hydroxymethyl-1-phenyl)-2-methyl-

cyclohexylidene]methyl N,N-Diisopropylcarbamate (6de)

According to GP1, allyl carbamate 1d (297 mg, 1.17 mmol) and

(–)-sparteine (328 mg, 1.40 mmol) were dissolved in toluene (3 mL)

and cooled to –78 °C before 1.6 M n-BuLi (0.88 mL, 1.40 mmol)

was added. The reaction mixture was stirred for 1 h after which 1.0

M Cl-TiPT solution in toluene (3.51 mL, 3.51 mmol) was added.

The dark solution was stirred for 1 h at –78 °C and then benzalde-

hyde (4e, 124 mg, 1.17 mmol), dissolved in toluene (1.0 mL), was

added. Flash chromatography yielded 6de (139 mg, 34%) as a co-

Anal. Calcd for C₁₉H₃₅NO₃(325.49): C, 70.11; H, 10.84; N, 4.30.

Found: C, 69.76; H, 10.97; N, 4.41.

Carbamate rac-6db was prepared by applying the analogous proce-

dure with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1d (622

mg, 2.45 mmol) gave rac-6db (639 mg, 80%).

{1Z,1[2S,2(1R)]}-1-[2-(1-Hydroxybutyl)-2-methylcyclohexyl-

idene]methyl N,N-Diisopropylcarbamate (6dc)

According to GP1, allyl carbamate 1d (329 mg, 1.30 mmol) and

(–)-sparteine (366 mg, 1.56 mmol) were dissolved in toluene (5 mL)

and cooled to –78 °C before 1.6 M n-BuLi (0.98 mL, 1.56 mmol)

was added. The reaction mixture was stirred for 1 h after which 1.0

M Cl-TiPT solution in toluene (4.7 mL, 4.7 mmol) was added. The

dark solution was stirred for 1 h at –78 °C and then n-butanal (4c,

141 mg, 1.95 mmol), dissolved in toluene (1 mL), was added. After

workup, the residue was purified by flash chromatography (petro-

leum ether–Et₂O, 7:1) to give 6dc (107 mg, 25%) as a colourless oil;

20

lourless oil; R_f0.26 (petroleum ether–Et₂O, 4:1); [a]_D= –34.3

(92% ee).

¹H NMR (300 MHz, CDCl₃): d = 1.13 (s, 3 H), 1.15–1.47 (m, 14 H),

1.53–1.65 (m, 1 H), 1.71–1.91 (m, 2 H), 2.09–2.35 (m, 3 H), 3.40–

4.40 (m, 2 H), 5.07 (s, 1 H), 6.98 (d, J = 1.7 Hz, 1 H), 7.21–7.40 (m,

5 H).

¹³C NMR (75 MHz, CDCl₃): d = 18.0 (CH₃), 21.0 (CH₃), 21.6

(CH₃), 22.7 (CH₂), 24.2 (CH₂), 26.8 (CH₂), 28.3 (CH₂), 29.4 (CH)

36.9 (CH), 45.2 (CH), 77.8 (CH), 125.8 (C_q), 132.2 (CH), 156.6

(C=O).

20

R_f0.33 (petroleum ether–Et₂O, 7:1); [a]_D= +61.7 (c = 0.36,

CHCl₃); GC: Supelco b-Dex 120 (77% ee); major enantiomer ap-

pears at lower retention time.

IR (film): 3508 (OH), 1700 (C=O) cm^–1.

Anal. Calcd for C₂₂H₃₃NO₃(359.51): C, 73.50; H, 9.25; N, 3.90.

Found: C, 73.31; H, 9.20; N, 3.85.

¹H NMR (300 MHz, CDCl₃): d = 0.93 (t, J = 7.0 Hz, 3 H), 1.05–1.79

(m, 22 H), 1.19 (s, 3 H), 1.99–2.26 (m, 2 H), 3.58 [4.14] (br s, 2 H),

3.88 (dd, J = 2.5, 8.9 Hz, 1 H), 6.89 (d, J = 1.4 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 14.2 (CH₃), 20.4 (CH₂), 20.7

(CH₃), 20.7 (CH₃), 21.2 (CH₂), 26.8 (CH₂), 29.0 (CH₂), 31.9 (CH₂),

36.4 (CH₂), 44.0 (C_q), 46.5 (CH), 72.4 (CH), 124.1 (C_q), 132.1

(CH), 152.3 (C=O).

Carbamate rac-6de was prepared by applying the analogous proce-

dure with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1d (137

mg, 0.54 mmol) gave rac-6de (165 mg, 85%).

{1Z,1[2S,2(1R)]}-1-[2-(1-Hydroxy-2-propenyl)-2-methylcyclo-

hexylidene]methyl N,N-Diisopropylcarbamate (6df)

According to GP1, allyl carbamate 1d (820 mg, 3.24 mmol) and

(–)-sparteine (909 mg, 3.88 mmol) were dissolved in toluene (10

mL) and cooled to –78 °C before 1.6 M n-BuLi (2.43 mL, 3.88

mmol) was added. The reaction mixture was stirred for 1 h after

which Cl-TiPT (3.03 g 11.6 mmol), dissolved in toluene (1 mL),

was added. The dark solution was stirred for 1 h at –78 °C and then

2-propenal (4f, 272 mg, 4.86 mmol), dissolved in toluene (1 mL),

was added. After workup, the residue was purified by flash chroma-

Anal. Calcd for C₁₉H₃₅NO₃(325.49): C, 70.11; H, 10.84; N, 4.30.

Found: C, 70.00; H, 11.02; N, 4.40.

Carbamate rac-6dc was prepared by applying the analogous proce-

dure with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1d (622

mg, 2.45 mmol) gave rac-6dc (674 mg, 83%).

Synthesis 2004, No. 14, 2303–2316 © Thieme Stuttgart · New York

2310

M. Özlügedik et al.

PAPER

tography (petroleum ether–Et₂O, 4:1) to give 6df (342 mg, 34%) as

mL), was added. After workup, the residue was purified by flash

chromatography (petroleum ether–Et₂O, 40:1) to give 6dh (87 mg,

27%) as red oil, which crystallised after 2 weeks at r.t.; R_f0.22 (pe-

troleum ether–EtOAc, 6:1); [a]_D= +166 (c = 0.40, CHCl₃): mp

135 °C (petroleum ether–Et₂O).

a colourless oil, which crystallised after 2 weeks at r.t.; R_f0.22 (pe-

20

troleum ether–EtOAc, 6:1); [a]_D= +30.4 (c = 0.40, CHCl₃).

20

HPLC: b-Dextrin-column (b-Dex 120) (82% ee); the major enanti-

omer appears at lower retention time.

IR (film): 3483 (OH), 1712 (C=O) cm^–1.

IR (KBr): 3484 (OH), 1683 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.96–2.23 (m, 23 H), 3.56 [4.18]

(br s, 2 H), 4.42 (d, J = 6.7 Hz, 1 H), 5.12 (d, J = 10.5 Hz, 1 H), 5.28

(d, J = 17.3 Hz, 1 H), 5.84 (dddd, J = 2.5, 6.7, 10.5, 17.3 Hz, 1 H),

6.89 (s, 1 H).

¹H NMR (300 MHz, CDCl₃): d = 1.09 (s, 3 H), 1.10–1.39 (m, 18 H),

1.99–2.06 (m, 1 H), 2.07 (d, J = 1.5 Hz, 1 H), 2.11–2.22 (m, 1 H),

3.58 [3.98–4.43] (br s, 2 H), 4.08–4.13 (m, 2 H), 4.15–4.20 (m, 6 H),

4.27–4.30 (m, 1 H), 4.73 (s, 1 H), 6.91 (d, J = 1.8 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 20.7 (CH₃), 21.4 (CH₃), 21.2

(CH₂), 26.7 (CH₂), 29.1 (CH₂), 36.4 (CH₂), 43.7 (C_q), 45.6 [47.1]

(CH), 74.3 (CH), 117.1 (CH₂), 124.2 (C_q), 132.3 (CH), 136.3 (CH),

152.3 (C=O).

¹³C NMR (75 MHz, CDCl₃): d = 20.8 (CH₃), 21.2 (CH₂), 22.1

(CH₃), 26.4 (CH₂), 29.2 (CH₂), 36.0 (CH₂), 43.6 (C_q), 45.5 (CH),

66.6 (CH), 67.3 (CH), 67.3 (CH), 68.5 (CH), 69.0 (CH), 72.2 (CH),

89.5(C_q), 124.3 (C_q), 131.7 (CH), 152.2 (C=O).

Anal. Calcd for C₁₈H₃₁NO₃(309.44): C, 69.86; H, 10.10; N, 4.53.

Found: C, 69.67; H, 10.23; N, 4.54.

Anal. Calcd for C₂₆H₃₇FeNO₃(467.43): C, 66.81; H, 7.98; N, 3.00.

Found: C, 66.92; H, 7.87; N, 2.84.

Carbamate rac-6df was prepared by applying the analogous proce-

dure with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1d (760

mg, 3.0 mmol) gave rac-6df (529 mg, 57%).

{1Z,1[2S,2(1S)]}-1-{[2-(4-Bromophenyl)-1-hydroxy]-2-methyl-

cycloheptylidene}methyl N,N-Diisopropylcarbamate (6ei)

According to GP1, allyl carbamate 1e (188 mg, 0.70 mmol) and

(–)-sparteine (196 mg, 0.84 mmol) were dissolved in toluene (5 mL)

and cooled to –78 °C before 1.32 M s-BuLi (0.64 mL, 0.84 mmol)

was added. The reaction mixture was stirred for 15 min after which

Cl-TiPT (657 mg, 2.52 mmol), dissolved in toluene (1 mL), was

added. The dark solution was stirred for 1 h at –78 °C and then p-

bromobenzaldehyde (4i, 194 mg, 1.05 mmol), dissolved in toluene

(1 mL), was added. After workup, the residue was purified by flash

chromatography (petroleum ether–Et₂O, 40:1) to give 6ei (87 mg,

27%) as a colourless solid; R_f0.08 (petroleum ether–Et₂O, 20:1);

{1Z,1[2S,2(1R)]}-1-{2-[1-Hydroxy-1-(1-naphthyl)methyl]-2-

methylcyclohexylidene}methyl N,N-Diisopropylcarbamate

(6dg)

According to GP1, allyl carbamate 1d (329 mg, 1.30 mmol) and

(–)-sparteine (366 mg, 1.56 mmol) were dissolved in toluene (5 mL)

and cooled to –78 °C before 1.6 M n-BuLi (0.98 mL, 1.56 mmol)

was added. The reaction mixture was stirred for 1 h after which 1.0

M Cl-TiPT solution in toluene (4.7 mL, 4.7 mmol) was added. The

dark solution was stirred for 1 h at –78 °C and then naphthalene-1-

carbaldehyde (4g, 314 mg, 1.95 mmol, 97 proc.), dissolved in tolu-

ene (1 mL), was added. After workup, the residue was purified by

flash chromatography (petroleum ether–Et₂O, 4:1) to give 6dg (177

mg, 33%) as a colourless oil; R_f0.14 (petroleum ether–CH₂Cl₂–

EtOAc, 32:7:1); –[a]_D²⁰= +6.8 (c = 0.44, CHCl₃). Shift experiment:

er 88.0:12.0 (76% ee), 11.6 mg + 21 mol% Eu(hfc)₃in CDCl₃, Dd

(Ar-H at 8.32 ppm) = 0.18 ppm; major enantiomer appears at lower

field.

20

[a]_D= +34.4 (c = 0.22, CHCl₃). Shift experiment: er 74.9:25.1

(50% ee), 6.2 mg + 7.3 mol% Eu(hfc)₃in CDCl₃, Dd (H at 4.64

ppm); mp 166 °C (petroleum ether–Et₂O).

IR (KBr): 3445 (OH), 1691 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.98–1.75 (m, 20 H), 1.37 (s, 3 H),

1.75–2.88 (m, 1 H), 1.94–2.07 (m, 1 H), 2.25 (s, 1 H), 3.68 [4.11]

(br s, 2 H), 4.64 (s, 1 H), 6.94 (s, 1 H), 7.20 (m_c, 2 H), 7.38 (m_c, 2 H).

¹³C NMR (75 MHz, CDCl₃): d = 20.8 (2 × CH₃), 22.3 (CH₃), 23.6

(CH₂), 29.9 (CH₂), 31.8 (CH₂), 32.0 (CH₂), 35.8 (CH₂), 46.5 (CH),

46.5 (C_q), 78.9 (CH), 121.1 (C_q), 128.4 (C_q), 129.8 (CH), 130.4

(CH), 135.4 (CH), 140.0 (C_q), 152.0 (C=O).

IR (KBr): 3490 (OH), 1687 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.90–1.61 (m, 20 H), 1.22 (s, 3 H),

3.52 [3.95] (br s, 2 H), 5.80 (s, 1 H), 6.98 (d, J = 1.3 Hz, 1 H), 7.34–

7.50 (m, 3 H), 7.71 (d, J = 7.4 Hz, 1 H), 7.76 (d, J = 8.1 Hz, 1 H),

7.79–7.86 (m, 1 H), 8.32 (d, J = 7.9 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 20.7 (CH₃), 23.4 (CH₃), 22.4

(CH₂), 26.6 (CH₂), 30.1 (CH₂), 37.4 (CH₂), 45.5 (C_q), 73.4 (CH),

124.4(C_q), 124.6 (C_q), 124.9 (CH), 125.9 (CH), 125.3 (CH), 126.8

(CH), 128.0 (CH), 128.8 (CH), 132.4 (CH), 132.4 (CH), 132.4 (C_q),

133.9 (C_q), 152.0 (C=O).

Anal. Calcd for C₂₃H₃₄BrNO₃(452.43): C, 61.06; H, 7.57; N, 3.10.

Found: C, 61.88; H, 7.73; N, 2.84.

Carbamate rac-6ei was prepared by applying the analogous proce-

dure with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1e (294

mg, 1.1 mmol) gave rac-6ei (323 mg, 71%).

{1Z,1[2S,2(1S)]}-1-{[2-(4-Bromophenyl)-1-hydroxy]-2-methyl-

cyclooctylidene}methyl N,N-Diisopropylcarbamate (6fi)

Anal. Calcd for C₂₆H₃₅NO₃(409.56): C, 76.25; H, 8.61; N, 3.42.

Found: C, 76.43; H, 8.70; N, 3.26.

According to GP1, allyl carbamate 1f (197 mg, 0.70 mmol) and

(–)-sparteine (196 mg, 0.84 mmol) were dissolved in toluene (5 mL)

and cooled to –78 °C before 1.32 M s-BuLi (0.64 mL, 0.84 mmol)

was added. The reaction mixture was stirred for 15 min after which

Cl-TiPT (657 mg, 2.52 mmol), dissolved in toluene (1 mL), was

added. The dark solution was stirred for 1 h at –78 °C and then p-

bromobenzaldehyde (4i, 194 mg, 1.05 mmol), dissolved in toluene

(1 mL), was added. After workup, the residue was purified by flash

chromatography (petroleum ether–Et₂O, 40:1) to give 6fi (66 mg,

21%) as a colourless solid; R_f0.12 (petroleum ether–Et₂O, 20:1);

Carbamate rac-6dg was prepared by applying the analogous proce-

dure with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1d (228 mg

(0.90 mmol) gave rac-6dg (198 mg, 57%).

{1Z,1[2S,2(1S)]}-1-[2-(1-Hydroxy-1-ferrocenylmethyl)-2-meth-

ylcyclohexylidene]methyl N,N-Diisopropylcarbamate (6dh)

According to GP1, allyl carbamate 1d (177 mg, 0.70 mmol) and

(–)-sparteine (212 mg, 0.91 mmol) were dissolved in toluene (5 mL)

and cooled to –78 °C before 1.6 M n-BuLi (0.57 mL, 0.91 mmol)

was added. The reaction mixture was stirred for 1 h after which Cl-

TiPT (710 mg, 2.73 mmol), dissolved in toluene (1 mL), was added.

The dark solution was stirred for 1 h at –78 °C and then ferrocene-

carbaldehyde (4h, 226 mg, 1.05 mmol), dissolved in toluene (1

20

[a]_D= +6.8 (c = 0.19, CHCl₃). Shift experiment: er = 68.3:31.7

(37% ee), 6.0 mg + 7.8 mol% Eu(hfc)₃in CDCl₃, Dd (H at 4.40

ppm); mp 66 °C (petroleum ether–Et₂O).

IR (KBr): 3462 (OH), 1693 (C = O) cm^–1.

Synthesis 2004, No. 14, 2303–2316 © Thieme Stuttgart · New York

PAPER

Stereoselective Synthesis of Highly Substituted Bicyclic g-Lactones

2311

¹H NMR (300 MHz, CDCl₃): d = 1.03–1.95 (m, 23 H), 1.27 (s, 3 H),

2.08–2.22 (m, 1 H), 2.22 (br s, 1 H, OH), 3.65 [4.08] (br s, 2 H), 4.40

(s, 1 H), 6.93 (s, 1 H), 7.19 (m_c, 2 H), 7.38 (m_c, 2 H).

¹³C NMR (75 MHz, CDCl₃): d = 19,5 (CH₃), 20.8 (2 × CH₃), 23.7

(CH₂), 25.0 (CH₂), 26.3 (CH₂), 29.4 (CH₂), 31.3 (CH₂), 33.9 (CH₂),

46.1 (C_q), 46.5 (CH), 79.2 (CH), 121.2 (C_q), 126.9 (C_q), 130.0 (CH),

130.4 (CH), 136.6 (CH), 139.6 (C_q), 152.3 (C=O).

rac-(3RS,3aSR,6aRS)-3-Methylhexahydrocyclopenta[c]furan-

1-one (rac-8aa)

According to GP3, rac-b-7aa (211 mg, 1.42 mmol) was oxidized

with m-CPBA (384 mg, 1.56 mmol, ca 60 proc.) and BF₃·OEt₂(199

mL, 1.42 mmol). After workup, the crude products were purified by

flash chromatography (petroleum ether–EtOAc, 1:2) to yield rac-

8aa (138 mg, 69%) as a colourless oil; R_f0.44 (petroleum ether–

EtOAc, 1:2).

Anal. Calcd for C₂₄H₃₆BrNO₃(466.45): C, 61.80; H, 7.78; N, 3.00.

Found: C, 61.54; H, 7.81; N, 2.83.

IR (film): 1767 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.35 (d, J = 6.3 Hz, 3 H), 1.39–

2.09 (m, 6 H), 2.49 (m_c, 1 H), 3.07 (m_c, 1 H), 4.21 (qd, J = 3.4, 6.3

Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 22.2 (CH₃), 25.4 (CH₂), 30.6

(CH₂), 33.1 (CH₂), 45.0 (CH), 46.7 (CH), 82.3 (CH), 180.3 (C=O).

Carbamate rac-6fi was prepared by applying the analogous proce-

dure with s-BuLi–TMEDA (1.2 equiv). Allyl carbamate 1f (321

mg, 1.14 mmol) gave rac-6fi (381 mg, 72%).

Converting Homoaldol Adducts 6 to Bicyclic Acetals 7; General

Procedure (GP2)

To a solution of 6 (1 mmol) and Hg(OAc)₂(0.05–0.20 mmol) in

MeOH (10 mL) at 0 ºC was added dropwise MeSO₃H (1–2 mmol)

and stirred at 0 ºC for 15 h. Solid NaHCO₃(2 equiv) was added to

the reaction mixture and the solvent was removed under reduced

pressure. The residue was dissolved in Et₂O (60 mL/mmol) and

washed with water (20 mL/mmol). The organic layer was dried with

MgSO₄and concentrated in vacuo.

rac-(3RS,3aSR,6aRS)-3-Isopropylhexahydrocyclopenta[c]fu-

ran-1-one (8ab)

According to GP2, 6ab (1.55 g, 5.25 mmol) was cyclized with

Hg(OAc)₂(169 mg, 0.53 mmol) and MeSO₃H (1.01 g, 10.5 mmol).

After workup, the organic layer was passed over silica gel. The sol-

vent was removed under reduced pressure to give of a mixture of

rac-a- and b-7ab (634 mg, 66%) which were used without further

purification. According to GP3 a mixture of rac-a- and b-7ab (336

mg, 1.82 mmol) was oxidized with m-CPBA (492 mg, 2.00 mmol,

ca 60 proc.) and BF₃·OEt₂(255 mL, 1.82 mmol). After workup, the

residue was purified by flash chromatography (petroleum ether–

Et₂O, 4:1) to give rac-8ab (244 mg, 73%) as a colourless oil: R_f0.36

(petroleum ether–Et₂O, 2:1).

Oxidation of Bicyclic Acetals 7 to Bicyclic Lactones 8; General

Procedure (GP3)

To a solution of acetal 7 (1.0 mmol) and m-CPBA (1.5–2.0 mmol,

ca 60 proc.) in CH₂Cl₂(5 mL), BF₃·OEt₂(1.0–2.7 mmol) was added

dropwise at 0 °C. After stirring at r.t. for 15 h, Me₂S (100 mL) was

added. The reaction mixture was stirred for an additional hour and

poured into mixture of Et₂O (20 mL) and water (10 mL). The aque-

ous layer was extracted with Et₂O (3 × 15 mL). The combined or-

ganic extracts were dried over anhyd MgSO₄and concentrated in

vacuo. The residue was purified by silica gel flash column chroma-

tography.

IR (film): 1769 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.91 (t, J = 6.3 Hz, 6 H), 1.44–1.90

(m, 6 H), 1.97–2.02 (m, 1 H), 2.58 (m_c, 1 H), 2.95 (dt, J = 3.0, 9.3

Hz, 1 H), 3.78 (dd, J = 3.9, 6.3 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 17.5 (CH₃), 25.4 (CH₂), 31.0

(CH₂), 33.3 (CH), 34.3 (CH₂), 42.1 (CH), 45.3 (CH), 91.3 (CH),

180.5 (C=O).

rac-(1SR,3RS,3aSR,6aRS)- and rac-(1RS,3RS,3aSR,6aRS)-1-

Methoxy-3-methyl-hexahydrocyclopenta[c]furan (rac-a-7aa)

and (rac-b-7aa)

According to GP2, rac-6aa (1.01 g, 3.80 mmol) was cyclised with

Hg(OAc)₂(242 mg, 0.76 mmol) and MeSO₃H (730 mg, 7.60

mmol). After workup, the crude products were purified by flash

chromatography (petroleum ether–Et₂O, 4:1) to give rac-a-7aa [97

mg (16%); R_f0.56 (petroleum ether–Et₂O, 4:1)] and rac-b-7aa [288

mg (49%); R_f0.47 (petroleum ether–Et₂O, 4:1)] as colourless oils.

Anal. Calcd for C₁₀H₁₆O₂(168.23): C, 71.39; H, 9.59. Found: C,

71.14; H, 9.76.

rac-(1SR,3RS,3aSR,6aRS)- and rac-(1RS,3RS,3aSR,6aRS)-1-

Methoxy-3-propyl-hexahydrocyclopenta[c]furan (rac-a-7ac)

and (rac-b-7ac)

According to GP2, rac-6ac (1.21 g, 4.10 mmol) was cyclized with

Hg(OAc)₂(261 mg, 0.82 mmol) and MeSO₃H (788 mg, 8.20

mmol). After workup, the crude products were purified by flash

chromatography (petroleum ether–Et₂O, 4:1) to yield rac-a-7ac

[159 mg (21%); R_f0.44 (petroleum ether–Et₂O, 4:1] and rac-b-7ac

[480 mg (64%); R_f0.54 (petroleum ether–Et₂O, 4:1] as colourless

oils.

rac-a-7aa

IR (film): 2953, 2879, 2829 (CH_aliph) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.25 (d, J = 6.2 Hz, 3 H), 1.21–

1.62 (2 × m, 6 H), 2.23 (m, 1 H), 2.77 (m_c, 1 H), 3.30 (s, 3 H), 3.59

(dq, J = 8.1 Hz, 6.2 Hz, 1 H), 4.87 (d, J = 6.3 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 19.8 (CH₃), 26.6 (CH₂), 27.5

(CH₂), 29.3 (CH₂), 49.5 (CH), 51.9 (CH), 54.8 (CH₃), 78.1 (CH),

105.8 (CH).

rac-a-7ac

IR (film): 2963, 2870, 2832 (CH_aliph) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.92 (t, J = 7.3 Hz, 3 H), 1.23–1.92

(m, 10 H), 2.23 (m_c, 1 H), 2.73 (m_c, 1 H), 3.30 (s, 3 H), 3.41–3.50

(m, 1 H), 4.85 (d, J = 6.0 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 14.2 (CH₃), 19.6 (CH₂), 26.4

(CH₂), 27.0 (CH₂), 29.9 (CH₂), 37.3 (CH₂), 49.4 (CH), 50.3 (CH),

54.6 (CH₃), 82.2 (CH), 105.5 (CH).

rac-b-7aa

IR (film): 2953, 2866, 2835 (CH_aliph) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.27 (d, J = 6.4 Hz, 3 H), 1.41–

1.80 (2 × m, 6 H), 2.38 (m_c, 1 H), 2.60 (m_c, 1 H), 3.30 (s, 3 H), 3.82

(dq, J = 4.4, 6.4 Hz, 1 H), 4.64 (d, J = 1.4 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 23.3 (CH₃), 25.8 (CH₂), 30.4

(CH₂), 32.5 (CH₂), 49.9 (CH), 51.6 (CH), 54.5 (CH₃), 83.7 (CH),

112.1 (CH).

Anal. Calcd for C₁₁H₂₀O₂(184.28): C, 71.95; H, 10.94. Found: C,

71.65; H, 10.84.

rac-b-7ac

IR (film): 2957, 2870, 2833 (CH_aliph) cm^–1.

2312

M. Özlügedik et al.

PAPER

¹H NMR (300 MHz, CDCl₃): d = 0.91 (t, J = 7.3 Hz, 3 H), 1.21–1.81

(m, 1 H), 2.42 (m_c, 1 H), 2.56 (m_c, 1 H), 3.29 (s, 3 H), 3.65 (ddd,

J = 4.3, 5.6, 7.8 Hz, 1 H), 4.65 (d, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 14.1 (CH₃), 19.7 (CH₂), 25.8

(CH₂), 30.4 (CH₂), 32.9 (CH₂), 40.2 (CH₂), 48.4 (CH), 51.5 (CH),

54.5 (CH₃), 87.9 (CH), 111.9 (CH).

ether–EtOAc, 1:2) to yield rac-8ad (380 mg, 83%) as a colourless

oil; R_f0.53 (petroleum ether–EtOAc, 1:2).

IR (film): 1770 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d= 0.85 (t, J = 6.9 Hz, 3 H), 1.13–2.10

(m, 20 H), 2.51 (dddd, J = 3.8, 3.8, 8.3, 9.0 Hz, 1 H), 2.99 (m_c, 1 H),

4.04 (ddd, J = 3.8, 5.7, 7.2 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 14.0 (CH₃), 22.6 (CH₂), 25.0

(CH₂), 25.5 (CH₂), 29.1 (CH₂), 29.4 (CH₂), 30.7 (CH₂), 31.8 (CH₂),

33.6 (CH₂), 36.6 (CH₂), 45.0 (CH), 45.0 (CH), 86.3 (CH), 180.5

(C=O).

rac-(3RS,3aSR,6aRS)-3-Propylhexahydrocyclopenta[c]furan-

1-one (rac-8ac)

According to GP3, a mixture of rac-a- and a-7ac (478 mg, 2.60

mmol) was oxidized with m-CPBA (704 mg, 2.86 mmol, ca 60

proc.) and BF₃·OEt₂(728 mL, 5.20 mmol). After workup, the crude

products were purified by flash chromatography (petroleum ether–

EtOAc, 1:2) to yield rac-8ac (311 mg, 71%) as a colourless oil; R_f

0.54 (petroleum ether–EtOAc, 1:2).

Anal. Calcd for C₁₅H₂₆O₂(238.37): C, 75.58; H, 10.99. Found: C,

75.43; H, 11.17.

rac-(3RS,3aRS,6aSR)-3-Phenylhexahydrocyclopenta[c]furan-

1-one (rac-8ae)⁸

IR (film): 1776 (C=O) cm^–1.

According to GP2, rac-6ae (1.19 g, 3.60 mmol), was cyclized with

Hg(OAc)₂(229 mg, 0.72 mmol) and MeSO₃H (692 mg, 7.20

mmol). The crude mixture of anomeric lactol ethers rac-7ae [316

mg (1.45 mmol) of the crude product (609 mg)] was oxidized (GP3)

with m-CPBA (394 mg, 1.60 mmol, content ca. 60 proc.) and

BF₃·OEt₂(406 mL, 2.90 mmol). After purification by silica gel chro-

matography (petroleum ether–Et₂O, 2:1) lactone rac-8ae (186 mg,

63%) was isolated as a colourless oil; R_f0.18 (petroleum ether–

Et₂O. 4:1).

IR (film): 1765 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.60–2.20 (m, 6 H), 2.85 (m, 1 H),

3.15 (m, 1 H), 5.10 (d, J = 3.6 Hz, 1 H), 7.25 (m, 5 H).

¹H NMR (300 MHz, CDCl₃): d = 0.92 (t, J = 7.2 Hz, 3 H), 1.28–2.09

3

(m, 10 H), 2.51 (m_c, 1 H), 2.99 (m_c, 1 H), 4.04 (ddd, J = 3.8, 5.4,

7.3 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 13.7 (CH₃), 18.3 (CH₂), 25.4

(CH₂), 30.7 (CH₂), 33.5 (CH₂), 38.7 (CH₂), 45.0 (CH), 45.0 (CH),

86.0 (CH), 180.5 (C=O).

rac-(1SR,3RS,3aSR,6aRS)- and rac-(1RS,3RS,3aSR,6aRS)-1-

Methoxy-3-octyl-hexahydrocyclopenta[c]furan (rac-a-7ad) and

(rac-b-7ad)

According to GP2, rac-6ad (1.31 g, 3.56 mmol) was cyclized with

Hg(OAc)₂(226 mg, 0.71 mmol) and MeSO₃H (684 mg, 7.10

mmol). After workup, the crude products were purified by flash

chromatography (petroleum ether–Et₂O, 10:1) to yield rac-a-7ad

[262 mg (29%); R_f0.43 (petroleum ether–Et₂O, 4:1)] and rac-b-7ad

[354 mg (39%); R_f0.52 (petroleum ether–Et₂O; 4:1)] as colourless

oils.

Anal. Calcd for C₁₃H₁₄O₂(202.26): C, 77.20; H, 6.98. Found: C,

77.12; H, 6.99.

(3R,3aS,6aR)-3-Isopropyl-3a-methylhexahydrocyclopen-

ta[c]furan-1-one (8bb)

20

According to GP2, 6bb (189 mg, 0.61 mmol, [a]_D= +29.6) was

rac-a-7ad

cyclized with Hg(OAc)₂(20 mg, 0.06 mmol) and MeSO₃H (117

mg, 1.22 mmol). The crude mixture of 7bb was oxidized according

to GP3 with m-CPBA (165 mg, 0.67 mmol, content ca. 60 proc.)

and BF₃·OEt₂(94 mL, 0.67 mmol). After flash chromatography (pe-

troleum ether–Et₂O, 1:2) of the crude product, 8bb was yielded (60

mg, 54%) as a colourless oil; R_f0.67 (petroleum ether–Et₂O, 1:2);

[a]_D²⁰= +21.3 (c = 0.15, CHCl₃).

¹H NMR (300 MHz, CDCl₃): d = 0.86 (t, J = 6.9 Hz, 3 H), 1.18–1.91

(m, 20 H), 2.22 (m_c, 1 H), 2.73 (dddd, J = 2.9, 6.1, 9.1, 10.5 Hz, 1

H), 3.40–3.49 (m, 1 H), 4.86 (d, J = 6.1 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 14.1 (CH₃), 22.7 (CH₂), 26.3

(CH₂), 26.4 (CH₂), 27.7 (CH₂), 29.3 (CH₂), 29.6 (CH₂), 29.8 (CH₂),

30.0 (CH₂), 31.9 (CH₂), 35.1 (CH₂), 49.4 (CH), 50.3 (CH), 54.6

(CH₃), 82.4 (CH), 105.5 (CH).

IR (film): 1771 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.97 (d, J = 6.8 Hz, 6 H), 1.16 (s,

3 H), 1.49–2.12 (m, 7 H), 2.52 (dd, J = 5.4, 8.9 Hz, 1 H), 3.83 (d,

J = 6.9 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 18.7 (CH₃), 20.0 (CH₃), 20.4

(CH₃), 25.4 (CH₂), 29.3 (CH₂), 29.5 (CH), 40.9 (CH₂), 50.1 (C_q),

53.7 (CH), 91.8 (CH), 179.8 (C=O).

Anal. Calcd for C₁₆H₂₀O₂(254.41): C, 75.54; H, 11.89. Found: C,

75.62; H, 12.03.

rac-b-7ad

IR (film): 2930, 2857, 2827 (CH_aliph) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.85 (t, J = 6.9 Hz, 3 H), 1.16–1.81

(m, 20 H), 2.36–2.46 (m, 1 H), 2.56 (m_c, 1 H), 3.30 (s, 3 H), 3.63

(ddd, J = 4.5, 5.9, 7.7 Hz, 1 H), 4.64 (d, J = 1.0, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 14.1 (CH₃), 22.6 (CH₂), 25.8

(CH₂), 26.5 (CH₂), 29.3 (CH₂), 29.6 (CH₂), 30.4 (CH₂), 31.9 (CH₂),

32.9 (CH₂), 38.0 (CH₂), 48.4 (CH), 51.5 (CH), 54.5 (CH₃), 88.3

(CH), 111.9 (CH).

EI–MS [C₁₆H₃₀O₂(254.41)]: m/z (%) = 254 (0.1) [M]⁺, 223 (8) [M

– OCH₃]⁺, 194 (7), 141 (100), 112 (17), 95 (8), 81 (49), 67 (19), 55

(11).

Anal. Calcd for C₁₁H₁₈O₂(182.13): C, 72.49; H, 9.95. Found:

C,72.16; H, 10.45.

(3R,3aS,6aR)-3a-Methyl-3-phenylhexahydrocyclopenta[c]fu-

ran-1-one (8be)

According to the GP2, 6be (139 mg, 0.42 mmol, 70% ee) was cy-

clized with Hg(OAc)₂(13 mg, 0.04 mmol) and MeSO₃H (81 mg,

0.84 mmol). After workup, the crude mixture of 7be was used with-

out further purification. According to GP3, 7be was oxidized with

m-CPBA (242 mg, 0.84 mmol, content ca. 60 proc.) and BF₃·OEt₂

(118 mL, 0.84 mmol). After workup, the crude products were puri-

fied by flash chromatography (petroleum ether–Et₂O, 4:1) to yield

8be (51 mg, 56% based on 6be) as a solid; R_f0.21 (petroleum ether–

rac-(3RS,3aSR,6aRS)-3-Octylhexahydrocyclopenta[c]furan-1-

one (rac-8ad)

According to GP3, a mixture of rac-a- and b-7ad and (491 mg, 2.60

mmol) was oxidized with m-CPBA (523 mg, 2.12 mmol, content ca

60 proc.) and BF₃·OEt₂(540 mL, 3.86 mmol). After workup, the

crude products were purified by flash chromatography (petroleum

20

Et₂O, 4:1); [a]_D= –6.2 (c = 1.34, CHCl₃); mp 58 °C (petroleum

ether–Et₂O).

IR (KBr): 1771 (C=O) cm^–1.

PAPER

Stereoselective Synthesis of Highly Substituted Bicyclic g-Lactones

2313

¹H NMR (300 MHz, CDCl₃): d = 0.72 (s, 3 H), 1.57–2.22 (m, 6 H), 0.52 mmol). The crude mixture of 7dd was oxidized according to

2.66 (dd, J = 3.6, 9.3 Hz, 1 H), 5.21 (s, 1 H), 7.15–7.39 (m, 5 H).

GP3 with m-CPBA (96 mg, 0.34 mmol, content ca. 60 proc.) and

BF₃·OEt₂(48 mL, 0.34 mmol). Purification by flash chromatogra-

phy (petroleum ether–Et₂O, 4:1) yielded 8dd (54 mg, 78%) as a co-

lourless oil; R_f0.38 (petroleum ether–Et₂O, 4:1); [a]_D= +25.4

(c = 0.34, CHCl₃).

¹³C NMR (75 MHz, CDCl₃): d = 22.7 (CH₃), 25.1 (CH₂), 29.5

(CH₂), 41.2 (CH₂), 51.6 (C_q), 51.8 (CH), 88.5 (CH), 125.6 (CH),

128.1 (CH), 128.7 (CH), 137.6 (C_q), 180.5 (C=O).

20

HRMS: m/z calcd C₁₄H₁₆O₂(216.28): 216.11504; found:

216.11564.

IR (film): 1777 (C=O) cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 0.85 (t, J = 7.0 Hz, 3 H), 1.05 (s,

3 H), 1.18–1.96 (2 × m, 22 H), 2.29 (t, J = 5.1 Hz, 1 H), 3.98 (dd,

J = 4.2, 9.3 Hz, 1 H).

(3R,3aS,6aR)-3-(4-Bromophenyl)-3a-methylhexahydrocyclo-

penta[c]furan-1-one (8bi)

According to GP2, 6bi (158 mg, 0.372 mmol, 79% ee) was cyclized

with Hg(OAc)₂(13 mg, 0.04 mmol) and MeSO₃H (81 mg, 0.84

mmol). After workup, 7bi was used without further purification.

According to GP3, the crude mixture of 7bi was oxidized with m-

CPBA (213 mg, 0.74 mmol, content ca. 60 proc.) and BF₃·OEt₂

(103 mL, 0.74 mmol) to yield 8bi (53 mg, 49%, based on 6bi) as co-

lourless crystals; mp 118 °C (petroleum ether–Et₂O); R_f0.20 (petro-

leum ether–Et₂O, 4:1); [a]_D²⁰= –3.0 (c = 0.50, CHCl₃).

¹³C NMR (100 MHz, CDCl₃): d = 14.0 (CH₃), 19.8 (CH₃), 21.4

(CH₂), 21.7 (CH₂), 22.6 (CH₂), 22.9 (CH₂), 26.3 (CH₂), 29.2 (CH₂),

29.4 (CH₂), 29.5 (CH₂), 29.5 (CH₂), 31.8 (CH₂), 34.4 (CH₂), 40.2

(C_q), 45.1 (CH), 86.7 (CH), 178.2 (C=O).

HRMS: m/z calcd C₁₇H₃₀O₂(266.42): 266.22458; found:

266.22421.

(3R,3aS,7aR)-3a-Methyl-3-(1-naphthyl)hexahydrobenzo[c]fu-

ran-1-one (8dg)

IR (KBr): 1766 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.73 (s, 3 H), 1.58–2.22 (m, 6 H), According to GP2, 8dg (116 mg, 0.28 mmol, 76% ee) was cyclized

2.63 (dd, J = 3.6, 9.3 Hz, 1 H), 5.16 (s, 1 H), 7.07 (m_c, 2 H), 7.48 with Hg(OAc)₂(10 mg, 0.03 mmol) and MeSO₃H (54 mg, 0.56

(m_c, 2 H).

mmol). The crude mixture of 7dg was oxidized according to GP3

with m-CPBA (148 mg, 0.60 mmol, content ca 60 proc.) and

BF₃·OEt₂(84 mL, 0.60 mmol). Purification by flash chromatogra-

phy (petroleum ether–EtOAc, 5:1) yielded 8dg (63 mg, 80%) as a

colourless oil; R_f= 0.44 (petroleum ether–Et₂O, 4:1); [a]_D²⁰= –85.5

(c = 0.40, CHCl₃); mp 189 °C (petroleum ether–EtOAc).

IR (KBr): 1778 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.72 (s, 3 H), 1.22–2.23 (m, 8 H),

2.56 (br s, 1 H), 5.97 (s, 1 H), 7.28–7.96 (3 × m, 7 H).

¹³C NMR (75 MHz, CDCl₃): d = 22.7 (CH₃), 25.2 (CH₂), 29.6

(CH₂), 41.1 (CH₂), 51.5 (C_q), 51.8 (CH), 87.7 (CH), 122.1 (C_q),

127.3 (CH), 131.6 (CH), 136.7 (C_q), 179.7 (C=O).

HRMS: m/z calcd C₁₄H₁₅BrO₂(295.17): 294.02554; found (for

C₁₄H₁₅⁷⁹BrO₂): 294.02394.

X-ray crystal structure analysis (Figure 1):¹²formula C₁₄H₁₅BrO₂,

M = 295.17, colourless crystal 0.50 × 0.10 × 0.10 mm, a = 7.342 (2),

b = 9.829 (2), c = 17.829 (5) Å, V = 1286.6 (6) Å³, r_calcd= 1.524 g

cm^–3, m = 42.52 cm^–1, empirical absorption correction via y scan ¹³C NMR (75 MHz, CDCl₃): d = 20.4 (CH₃), 21.1 (CH₂), 21.5

data (0.225 £ T £ 0.676), Z = 4, orthorhombic, space group P2₁2₁2₁(CH₂), 22.7 (CH₂), 36.1 (CH₂), 42.6 (C_q), 43.2 (CH), 84.7 (CH),

(No. 19), l = 1.54178 Å, T = 223 K, w/2q scans, 2966 reflections 122.8 (CH), 123.0 (CH), 125.2 (CH), 125.8 (CH), 126.2 (CH),

collected (–h, +k, ±l), [(sinq)/l] = 0.62 Å^–1, 2612 independent (R_int128.6 (CH), 129.1 (CH), 131.0 (C_q), 132.3 (C_q), 133.4 (C_q), 178.6

= 0.027) and 2481 observed reflections [I ≥ 2s(I)], 156 refined pa- (C=O).

rameters, R1 = 0.030, wR2 = 0.078, Flack parameter –0.01(2), max.

Anal. Calcd for C₁₉H₂₀O₂(280.36): C, 81.40; H, 7.19. Found: C,

81.09; H, 7.09.

residual electron density 0.60 (–0.47) e Å^–3, hydrogens calculated

and refined as riding atoms.

(3R,3aS,7aR)-3-(4-Bromophenyl)-3a-methylhexahydroben-

zo[c]furan-1-one (8di)

According to GP2, 6di (60 mg, 0.137 mmol, 87% ee) was cyclized

with Hg(OAc)₂(4.5 mg, 0.014 mmol) and MeSO₃H (26 mg, 0.27

mmol). The crude mixture of 7di was oxidized according to GP3

with m-CPBA (118 mg, 0.41 mmol, content ca. 60 proc.) and

rac-(3RS,3aSR,7aRS)-3a-Methyl-3-propylhexahydroben-

zo[c]furan-1-one (rac-8dc)

According to GP2, rac-6dc (511 mg, 1.57 mmol) was cyclized with

Hg(OAc)₂(25 mg, 0.08 mmol) and MeSO₃H (226 mg, 2.36 mmol).

After workup, the crude mixture of products was used without fur-

ther purification. The crude mixture rac-7dc was oxidized accord-

BF₃·OEt₂(51 mL, 0.36 mmol). After purification by flash chroma-

ing GP3 with m-CPBA (515 mg, 2.09 mmol, content ca. 60 proc.)

tography (petroleum ether–Et₂O, 1:2) 8di was yielded (31 mg, 73%)

and BF₃·OEt₂(220 mL, 1.57 mmol). Purification by flash chroma-

tography (petroleum ether–Et₂O, 4:1) yielded rac-8dc (232 mg,

75%) as a colourless oil; R_f0.29 (petroleum ether–Et₂O, 4:1).

IR (film): 1772 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.92 (t, J = 7.3 Hz, 3 H), 1.05 (s,

3 H), 1.20–1.96 (2 × m, 12 H), 2.29 (t, J = 5.0 Hz, 1 H), 3.99 (t, J =

6.4 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 13.8 (CH₃), 19.5 (CH₂), 19.8

(CH₃), 21.3 (CH₂), 21.7 (CH₂), 22.9 (CH₂), 31.5 (CH₂), 34.4 (CH₂),

40.1 (C_q), 45.0 (CH), 86.4 (CH), 178.3 (C=O).

20

as a colourless solid; R_f0.22 (petroleum ether–Et₂O, 4:1); [a]_D

–15.8 (c = 0.10, CHCl₃).

IR (KBr): 1781 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.74 (s, 3 H), 1.35–2.05 (m, 8 H),

2.37 (m_c, 1 H), 5.06 (s, 1 H), 7.03 (m_c, 2 H), 7.47 (m_c, 2 H).

¹³C NMR (75 MHz, CDCl₃): d = 21.4 (CH₃), 21.5 (CH₂), 21.9

(CH₂), 22.8 (CH₂), 34.8 (CH₂), 42.0 (C_q), 44.4 (CH), 86.4 (CH),

122.2 (C_q), 127.6 (CH), 131.5 (CH), 135.3 (C_q), 178.1 (C=O).

=

Anal. Calcd for C₁₅H₁₇BrO₂(309.20): C, 58.27; H, 5.54. Found: C,

58.08; H, 5.80.

Anal. Calcd for C₁₂H₂₀O₂(196.29): C, 73.43; H, 10.27. Found: C,

73.33; H, 10.28.

X-ray crystal structure analysis (Figure 2):¹²formula C₁₅H₁₇BrO₂,

M = 309.20, colourless crystal 0.30 × 0.20 × 0.20 mm, a = 13.749

(2), b = 7.353 (1), c = 13.993(2) Å, = 101.12(1), V = 1388.1 (3) Å³,

(3R,3aS,7aR)-3a-Methyl-3-octylhexahydro-benzo[c]furan-1-

one (8dd)

r

_calcd= 1.480 g cm^–3, m = 39.67 cm^–1, empirical absorption correc-

According to GP2, 6dd (104 mg, 0.26 mmol, ([a]_D²⁰= +45.4) was

cyclized with Hg(OAc)₂(10 mg, 0.03 mmol) and MeSO₃H (50 mg,

tion via y scan data (0.382 £ T £ 0.504), Z = 4, monoclinic, space

group P2₁(No. 4), l = 1.54178 Å, T = 223 K, w/2q scans, 3190 re-

2314

M. Özlügedik et al.

PAPER

flections collected (±h, –k, +l), [(sinq)/l] = 0.62 Å^–1, 3065 indepen-

dent (R_int= 0.025) and 2873 observed reflections [I ≥ 2s(I)], 328

refined parameters, R1 = 0.039, wR2 = 0.121, Flack parameter

0.03(3), max. residual electron density 0.49 (–0.63) e Å^–3, two al-

most identical molecules in the asymmetric unit, hydrogens calcu-

lated and refined as riding atoms.

[45.2] (C_q), 54.4 [48.0] (CH), 85.5 [86.6] (CH), 122.5 [122.4] (C_q),

129.0 [128.8] (CH), 131.4 [131.3] (CH), 134.2 [134.4] (C_q), 177.1

[179.4] (C=O).

ESI–MS: m/z calcd for C₁₇H₂₁BrO₂(337.25): 359, 361 [M + Na]⁺.

(3R,3aS,7aR)-3a-Methyl-3-vinylhexahydro-benzo[c]furan-1-

one (8df) from 6df via Vinyllithiation and Methanesulfenylation

To enol carbamate 6df (82% ee, 327 mg, 1.06 mmol), Et₃N (192

mg, 1.90 mmol) in CH₂Cl₂, chlorotrimethylsilane (172 mg, 1.59

mmol) was added at 0 °C. The mixture was stirred at 25 °C for 15 h

and subsequently poured to a mixture of Et₂O (10 mL) and sat. aq

NH₄Cl (10 mL). The Et₂O solution was separated and the aqueous

phase extracted with Et₂O (3 × 10 mL). The combined organic so-

lutions were neutralised with aq NaHCO₃solution (20 mL) and

dried (solid MgSO₄). The solvents were removed in vacuo and the

crude silyl ether 9 dissolved in toluene (10 mL). After renewed re-

moval of the solvent in vacuo, the residue was dissolved in anhyd

THF (5 mL) under Ar, TMEDA (148 mg, 1.25 mmol) was added,

and at –78 °C n-BuLi in hexane (1.51 mmol) was slowly introduced

through the septum with a syringe. Stirring was continued for 2 h

before dimethyl disulfide (150 mg, 1.59 mmol) was added at –78 °C

within 5 min. After having stirred at –78 °C for 3 h, the reaction

mixture was allowed to warm to 0 °C. The solution was extracted

with sat. aq NH₄Cl, and the aqueous phase extracted with Et₂O (3 ×

10 mL). The solvent of the combined organic solutions was evapo-

rated in vacuo. The remaining crude ketene monothio acetal 10, dis-

solved in MeOH (5 mL), and methane sulfonic acid (152 mg, 1.59

mmol) were heated to 50 °C for 15 h. The reaction mixture was al-

lowed to cool to r.t., poured to a mixture of Et₂O (10 mL) and 1 N

aq HCl. Separation of the Et₂O phase, extraction of the aq phase

with Et₂O (3 × 10 mL each), extraction of the combined ethereal so-

lutions with sat. NaHCO₃solution, drying over MgSO₄, and evapo-

ration led to crude g-lacton 8df. Chromatographic purification on

rac-(3RS,3aSR,8aRS)- and rac-(3RS,3aSR,8aSR)-3-(4-Bromo-

phenyl)-3a-methyloctahydrocyclohepta[c]furan-1-one [rac-

8ei(c)] and [rac-8ei(t)]

According to GP2, rac-6ei (179 mg, 0.40 mmol) was cyclized with

Hg(OAc)₂(6.4 mg, 0.02 mmol) and MeSO₃H (58 mg, 0.60 mmol).

The crude mixture of 7ei was oxidized according to GP3 with m-

CPBA (515 mg, 2.09 mmol, content ca. 60 proc.) and BF₃·OEt₂

(400 mL, 3.10 mmol). Purification by flash chromatography (petro-

leum ether–EtOAc, 20:1) yielded the cis-isomer rac-8ei(c) [(58 mg,

44%); R_f0.19 (petroleum ether–EtOAc, 20:1), mp 109 °C (petro-

leum ether–EtOAc)] and the trans isomer rac-8ei(t) [(29 mg, 23%);

R_f0.25 (petroleum ether–EtOAc, 20:1); mp 161 °C (petroleum

ether–EtOAc)]; NOE between 3a-CH₃and 8a-H.

rac-8ei(c)

IR (film): 1770 (C=O) cm^–1.

¹H NMR (400 MHz, C₆D₆): d = 0.26 (s, 3 H), 0.75–0.84 (m, 1 H),

0.89–0.98 (m, 2 H), 0.99–1.07 (m, 2 H), 1.19–1.26 (m, 1 H), 1.33

(m_c, 1 H), 1.48 (br s, 1 H), 1.65 (br s, 1 H), 1.79 (dd, J = 6.1, 14.1

Hz, 1 H), 2.03 (d, J = 12.1 Hz, 1 H), 4.55 (s, 1 H), 6.70 (m_c, 2 H),

7.22 (m_c, 2 H).

¹³C NMR (100 MHz, C₆D₆): d = 22.8 (CH₃), 23.2 (CH₂), 27.3

(CH₂), 30.4 (CH₂), 31.3 (CH₂), 37.0 (CH₂), 46.4 (C_q), 55.2 (CH),

87.3 (CH), 122.1 (C_q), 127.7 (CH), 131.5 (CH), 135.3 (C_q), 177.7

(C=O).

HR-MS: m/z calcd for C₁₆H₁₉BrO₂(323.22): 322.05685; found [for

silica gel (petroleum ether–Et₂O, 4:1) afforded 8df (106 mg, 56%)

C₁₆H₁₉⁷⁹BrO₂]: 322.05491.

20

as a colourless oil; R_f0.16 (petroleum ether–Et₂O, 4:1); [a]_D

=

rac-8ei(t)

enantiomer appears at lower retention time.

IR (KBr): 1767 (C=O) cm^–1.

IR (film): 1778 (C=O) cm^–1.

¹H NMR (400 MHz, C₆D₆): d = 0.21 (s, 3 H), 0.69–1.58 (m, 9 H),

2.00–2.14 (m, 2 H), 4.24 (s, 1 H), 6.73 (m_c, 2 H), 7.23 (m_c, 2 H).

¹³C NMR (100 MHz, C₆D₆): d = 14.1 (CH₃), 22.3 (CH₂), 25.2

(CH₂), 26.2 (CH₂), 26.6 (CH₂), 38.0 (CH₂), 48.1 (C_q), 49.1 (CH),

87.3 (CH), 122.2 (C_q), 128.2 (CH), 131.5 (CH), 134.8 (C_q), 176.5

(C=O).

¹H NMR (360 MHz, CDCl₃): d = 1.04 (s, 3 H), 1.19–2.01 (2 × m, 8

H), 2.28 (dd, J = 4.4, 5.4 Hz, 1 H), 4.42 (dYt, J = 1.3, 6.3 Hz, 1 H),

5.26 (dYt, J = 1.3, 10.6 Hz, 1 H), 5.30 (dYt, J = 1.3, 17.0 Hz, 1 H),

5.80 (ddd, J = 6.3, 10.6, 17.0 Hz, 1 H).

¹³C NMR (90 MHz, CDCl₃): d = 20.2 (CH₃), 21.3 (CH₂), 21.4

(CH₂), 22.7 (CH₂), 34.2 (CH₂), 41.0 (C_q), 44.3 (CH), 86.4 (CH),

118.2 (CH₂), 132.1 (CH), 178.1 (C=O).

HRMS: calcd C₁₆H₁₉BrO₂(323.22): 322.05685; found [for

C₁₆H₁₉⁷⁹BrO₂]: 322.05495.

Anal. Calcd for C₁₁H₁₆O₂(180.24): C, 73.30; H, 8.95; found: C,

72.97; H, 8.66.

rac-(3RS,3aSR,9aRS)- and rac-(3RS,3aSR,9aSR)-3-(4-Bromo-

phenyl)-3a-methyloctahydro-cycloocta[c]furan-1-one [rac-

8fi(c)] and [rac-8fi(t)]

Alkylation of Bicyclic Lactones; General Procedure (GP4)

1,1,1,3,3,3-Hexamethyldisilazane (1.05–2.10 mmol) was added

dropwise to 1.6 M n-BuLi (1.0–2.0 equiv) in hexane at 0 °C. The

cooling bath was removed and the reaction mixture was stirred for

15 min. Then, the solvent was removed at reduced pressure with ex-

clusion of moisture; the residue was dissolved in THF (5 mL) and

cooled to –78 °C. The lactone 8 (1.0 mmol), dissolved in THF (5

mL), was added and the mixture was stirred for 1 h at –78 °C before

the 2-naphthylmethyl bromide (1.05–2.10 mmol), dissolved in THF

(3 mL), was added. The reaction mixture was allowed to attain r.t.

for a period of 15 h and then was poured in a mixture of sat. NH₄Cl

solution (10 mL/mmol) and Et₂O (20 mL). The aqueous layer was

extracted with Et₂O (3 × 15 mL). The combined organic extracts

were dried over anhyd MgSO₄and concentrated in vacuo. The res-

idue was purified by silica gel flash column chromatography.

According to GP2, rac-6fi (233 mg, 0.48 mmol) was cyclized with

Hg(OAc)₂(7.6 mg, 0.024 mmol) and MeSO₃H (69 mg, 0.72 mmol).

According to GP3 the crude diastereomeric rac-7fi was oxidized

with m-CPBA (515 mg, 2.09 mmol, content ca. 60 proc.) and

BF₃·OEt₂(400 mL, 3.10 mmol). Purification by flash chromatogra-

phy (petroleum ether–EtOAc, 20:1) yielded a inseparable mixture

of diastereomers rac-8fi(c) and rac-fi(t) (103 mg, 62%); R_f0.12

(petroleum ether–EtOAc, 20:1); ratio 25:75, as a colourless solid;

chemical shift of minor diastereomer in parenthesis.

¹H NMR (400 MHz, C₆D₆): d = 0.25 [0.31] (s, 3 H), 0.59–2.24 (m,

13 H), 4.31 [4.46] (s, 1 H), 6.70–6.79 (m, 2 H), 7.19–7.27 (m, 2 H).

¹³C NMR (100 MHz, C₆D₆): d = 16.0 [19.7] (CH₃), 22.7 (CH₂), 24.3

(CH₂), 24.5 (CH₂), 24.6 (CH₂), 25.3 (CH₂), 26.2 (CH₂), 26.9 (CH₂),

27.0 (CH₂), 27.8 (CH₂), 30.5 (CH₂), 31.8 (CH₂), 36.3 (CH₂), 46.3

PAPER

Stereoselective Synthesis of Highly Substituted Bicyclic g-Lactones

2315

rac-(3RS,3aSR,6aSR)-3-Methyl-6a-(2-naphthylmethyl)hexahy-

drocyclopenta[c]furan-1-one (rac-12a)

(ddd, J =4.5, 6.2, 7.6 Hz, 1 H), 7.31 (dd, J = 1.8, 8.5 Hz, 1 H), 7.43

(m_c, 2 H), 7.62 (br s, 1 H), 7.74–7.81 (m, 3 H).

According to GP4, 1,1,1,3,3,3-hexamethyldisilazane (163 mg, 1.01

mmol) was deprotonated with n-BuLi (0.60 mL, 0.96 mmol). Com-

pound rac-8aa (90 mg, 0.64 mmol) was added and the enolate was

quenched with 2-bromomethyl-naphthalene (170 mg, 0.77 mmol).

After purification by flash chromatography (petroleum ether–

EtOAc, 5:1) rac-12a (80 mg, 45%) was obtained as a colourless sol-

id; R_f0.56 (petroleum ether–EtOAc, 5:1); mp 93 °C (petroleum

ether–EtOAc).

¹³C NMR (75 MHz, CDCl₃): d = 13.4 (CH₃), 18.2 (CH₂), 25.3

(CH₂), 34.0 (CH₂), 37.6 (CH₂), 39.5 (CH₂), 42.7 (CH₂), 47.3 (CH),

58.4 (C_q), 85.4 (CH), 125.7 (CH), 126.1 (CH), 127.5 (CH), 127.6

(CH), 128.1 (CH), 128.3 (CH), 128.8 (CH), 132.5 (C_q), 133.4 (C_q),

135.4 (C_q), 182.1 (C=O).

Anal. Calcd for C₂₁H₂₄O₂(308.41): C, 81.78; H, 7.84. Found: C,

81.64; H, 8.12.

IR (KBr):1755 (C=O) cm^–1.

rac-(3RS,3aSR,6aSR)-6a-(2-Naphthylmethyl)-3-octylhexahy-

drocyclopenta[c]furan-1-one (rac-12d)

¹H NMR (300 MHz, CDCl₃): d = 0.67 (d, J = 6.4 Hz, 3 H), 1.44–

2.32 (2 × m, 6 H), 2.36 (dd, J = 4.6, 6.7 Hz, 1 H), 2.79 (d, J = 13.6

Hz, 1 H), 3.50 (d, J = 13.6 Hz, 1 H), 3.95 (qd, J = 4.6, 6.4 Hz, 1 H),

7.32 (dd, J = 1.7, 8.2 Hz, 1 H), 7.43 (m_c, 2 H), 7.64 (br s, 1 H), 7.74–

7.81 (m, 3 H).

¹³C NMR (75 MHz, CDCl₃): d = 21.2 (CH₃), 25.2 (CH₂), 33.7

(CH₂), 39.9 (CH₂), 42.7 (CH₂), 48.9 (CH), 58.8 (C_q), 81.8 (CH),

125.7 (CH), 126.1 (CH), 127.6 (CH), 127.7 (CH), 128.1 (CH),

128.3 (CH), 128.8 (CH), 132.4 (C_q), 133.4 (C_q), 135.4 (C_q), 182.0

(C=O).

According to GP4, 1,1,1,3,3,3-hexamethyldisilazane (204 mg, 1.26

mmol) was deprotonated with n-BuLi (0.75 mL, 1.20 mmol). Com-

pound rac-8ad (286 mg, 1.20 mmol) was added and the enolate was

quenched with 2-bromomethyl-naphthalene (292 mg, 1.32 mmol).

After purification by flash chromatography (petroleum ether–

EtOAc, 10:1) rac-12d (218 mg, 48%) was obtained as a colourless

solid; R_f0.27 (petroleum ether–EtOAc, 10:1); mp 71 °C (petroleum

ether–EtOAc).

IR (KBr): 1749 (C=O) cm^–1.

Anal. Calcd for C₁₉H₂₀O₂(280.36): C, 81.40; H, 7.19. Found: C,

81.21; H, 6.95.

¹H NMR (300 MHz, CDCl₃): d = 0.58–2.31 (3 × m, 20 H), 0.86 (t,

J = 7.0 Hz, 3 H), 2.38 (dd, J = 4.4, 7.2 Hz, 1 H), 2.76 (d, J = 13.5

Hz, 1 H), 3.49 (d, J = 13.5 Hz, 1 H), 3.76 (ddd, J = 4.4, 6.3, 7.3 Hz,

1 H), 7.31 (dd, J = 1.9, 8.6 Hz, 1 H), 7.42 (m_c, 2 H), 7.62 (br s, 1 H),

7.70–7.82 (m, 3 H).

rac-(3RS,3aSR,6aSR)-3-Isopropyl-6a-(2-naphthylmethyl)hexa-

hydrocyclopenta[c]furan-1-one (rac-12b)

According to GP4, 1,1,1,3,3,3-hexamethyldisilazane (144 mg, 0.89

mmol) was deprotonated with n-BuLi (0.53 mL, 0.85 mmol). Com-

pound rac-8ab (142 mg, 0.85 mmol) was added and the enolate was

quenched with 2-bromomethyl-naphthalene (208 mg, 0.94 mmol).

After purification by flash chromatography (petroleum ether–

EtOAc, 20:1) rac-12b (110 mg, 42%) was obtained as a colourless

solid; R_f0.12 (petroleum ether–EtOAc, 20:1); mp 79 °C (petroleum

ether–EtOAc).

¹³C NMR (75 MHz, CDCl₃): d = 14.0 (CH₃), 22.6 (CH₂), 24.7

(CH₂), 25.2 (CH₂), 29.0 (CH₂), 31.7 (CH₂), 34.1 (CH₂), 35.3 (CH₂),

39.7 (CH₂), 42.7 (CH₂), 47.1 (CH), 58.4 (C_q), 85.7 (CH), 125.7

(CH), 126.0 (CH), 127.5 (CH), 127.6 (CH), 128.1 (CH), 128.3

(CH), 128.7 (CH), 132.4 (C_q), 133.4 (C_q), 135.4 (C_q), 182.0 (C=O).

Anal. Calcd for C₂₆H₃₄O₂(378.55): C, 82.49; H, 9.05. Found: C,

82.47; H, 9.17.

IR (KBr): 1763 (C=O) cm^–1.

rac-(3RS,3aSR,6aSR)-6a-(2-Naphthylmethyl)-3-phenylhexahy-

drocyclopenta[c]furan-1-one (rac-12e)

¹H NMR (300 MHz, CDCl₃): d = 0.57 (d, J = 6.7 Hz, 3 H), 0.62 (d,

J = 6.7 Hz, 3 H), 0.96 (sept, J = 6.7 Hz, 1 H), 1.47–2.30 (3 × m, 6

H), 2.49 (m_c, 1 H), 2.80 (d, J = 13.6 Hz, 1 H), 3.44 (d, J = 13.6 Hz,

1 H), 3.48 (m_c, 1 H), 7.31 (dd, J = 1.8, 8.5 Hz, 1 H), 7.43 (m_c, 2 H),

7.63 (br s, 1 H), 7.67–7.83 (m, 3 H).

¹³C NMR (75 MHz, CDCl₃): d = 17.4 (CH₃), 18.0 (CH₃), 25.1

(CH₂), 32.7 (CH), 33.8 (CH₂), 39.2 (CH₂), 42.5 (CH₂), 45.4 (CH),

58.1 (C_q), 90.2 (CH), 125.6 (CH), 126.0 (CH), 127.5 (CH), 127.6

(CH), 128.0 (CH), 128.3 (CH), 128.8 (CH), 132.4 (C_q), 133.4 (C_q),

135.4 (C_q), 181.9 (C=O).

According to GP4, 1,1,1,3,3,3-hexamethyldisilazane (163 mg, 1.01

mmol) was deprotonated with n-BuLi (0.60 mL, 0.96 mmol). Com-

pound rac-8ae (127 mg, 0.63 mmol) was added and the enolate was

quenched with 2-bromomethyl-naphthalene (170 mg, 0.77 mmol).

Purification by flash chromatography (petroleum ether–EtOAc,

5:1) yielded rac-12e (160 mg, 46%) as a colourless solid; R_f0.35

(petroleum ether–EtOAc, 5:1); mp 123 °C (petroleum ether–

EtOAc).

IR (KBr): 1754 (C=O) cm^–1.

HRMS: m/z calcd for C₂₁H₂₄O₂(308.41): 308.17764; found:

308.17700.

¹H NMR (300 MHz, CDCl₃): d = 1.53–2.49 (2 × m, 6 H), 2.65–2.87

(m, 2 H), 3.49 (d, J = 13.4 Hz, 1 H), 4.77 (d, J = 5.3 Hz, 1 H), 6.36–

7.87 (6 × m, 12 H).

¹³C NMR (75MHz, CDCl₃): d = 25.0 (CH₂), 33.3 (CH₂), 39.4 (CH₂),

42.6 (CH₂), 51.0 (CH), 58.5 (C_q), 85.6 (CH), 124,7 (CH), 125.6

(CH), 126.0 (CH), 127.4 (CH), 127.6 (CH), 127.7 (CH), 128.1

(CH), 128.2 (CH), 128.4 (CH), 128.9 (CH), 132.5 (C_q), 133.4 (C_q),

134.9 (C_q), 140.1 (C_q), 181.8 (C=O).

rac-(3RS,3aSR,6aSR)-6a-(2-Naphthylmethyl)-3-propylhexahy-

drocyclopenta[c]furan-1-one (rac-12c)

According to GP4, 1,1,1,3,3,3-hexamethyldisilazane (202 mg, 1.25

mmol) was deprotonated with n-BuLi (0.74 mL, 1.19 mmol). Com-

pound rac-8ac (200 mg, 1.19 mmol) was added and the enolate was

quenched with 2-bromomethyl-naphthalene (290 mg, 1.31 mmol).

After workup, the crude products were purified by flash chromatog-

raphy (petroleum ether–EtOAc, 5:1) to yield rac-12c (167 mg,

46%) as a colourless solid; R_f0.57 (petroleum ether–EtOAc, 5:1);

mp 72 °C (petroleum ether–EtOAc).

HRMS: m/z calcd for C₂₁H₂₂O₂(342.43): 342.16199; found:

342.16239.

rac-(3RS,3aSR,7aSR)-3a-Methyl-7a-(2-naphthylmethyl)-3-pro-

pylhexahydro[c]benzofuran-1-one (rac-12f)

IR (KBr): 1755 (C=O) cm^–1.

According to GP4, 1,1,1,3,3,3-hexamethyldisilazane (282 mg, 1.75

mmol) was deprotonated with n-BuLi (1.04 mL, 1.66 mmol). Com-

pound rac-8bc (162 mg, 0.83 mmol) was added and the enolate was

quenched with 2-bromomethyl-naphthalene (275 mg, 1.25 mmol).

After purification by flash chromatography (petroleum ether–

¹H NMR (300 MHz, CDCl₃): d = 0.53 (t, J = 7.4 Hz, 3 H), 0.59–0.85

(m, 2 H), 0.92–1.18 (m, 2 H), 1.44–2.30 (3 × m, 6 H), 2.34–2.42 (m,

1 H), 2.78 (d, J = 13.6 Hz, 1 H), 3.48 (d, J = 13.6 Hz, 1 H), 3.79

2316

M. Özlügedik et al.

PAPER

Reagents in Organic Synthesis, 1st ed.; Springer-Verlag:

Berlin, 1986. (b) Weidmann, B.; Seebach, D. Angew.

Chem., Int. Ed. Engl. 1983, 22, 32; Angew. Chem. 1983, 95,

12. (c) Reetz, M. T. In Organotitanium Chemistry,

Organometallics in Synthesis; Schlosser, M., Ed.; Wiley:

Chichester, 2002, 817.

EtOAc, 20:1) rac-12e was yielded (145 mg, 52%) as a colourless

solid; R_f0.24 (petroleum ether–EtOAc, 20:1); mp 129 °C (petro-

leum ether–EtOAc).

IR (KBr): 1759 (C=O) cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.89–1.12 (m, 6 H), 1.16–1.80 (m,

12 H), 2.81 (d, J = 14.2 Hz, 1 H), 3.20 (d, J = 14.2 Hz, 1 H), 4.53

(dd, J = 9.7, 1.8 Hz, 1 H), 7.32–7.95 (2 × m, 7 H).

(6) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957,

79, 1920.

¹³C NMR (75 MHz, CDCl₃): d = 14.0 (CH₃), 18.6 (CH₃), 20.4

(CH₂), 20.8 (CH₂), 21.2 (CH₂), 27.0 (CH₂), 30.5 (CH₂), 31.5 (CH₂),

36.2 (CH₂), 44.5 (C_q), 49.5 (C_q), 81.7 (CH), 125.4 (CH), 125.4

(CH), 127.4 (CH), 127.5 (CH), 127.7 (CH), 129.7 (CH), 129.8

(CH), 132.3 (C_q), 133.3 (C_q), 135.0 (C_q), 180.5 (C=O).

(7) In related cases, we recently observed an oxidative dimer of

1. We suspect that a one-electron transfer from titanium to

the allylic anion is the cause. The use of ClTi(NEt₂)₃as

exchange reagent is recommended.^3d

(8) Hoppe, D.; Hanko, R. Angew. Chem., Int. Ed. Engl. 1982,

21, 372; Angew. Chem. 1982, 94, 378.

(9) (a) Hoppe, D.; Brönneke, A. Tetrahedron Lett. 1983, 24,

1687. (b) Hanko, R.; Rabe, K.; Dally, R.; Hoppe, D. Angew.

Chem., Int. Ed. Engl. 1991, 30, 1690; Angew. Chem. 1991,

103, 1725.

(10) Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett.

1978, 419.

(11) Paulsen, H.; Hoppe, D. Tetrahedron 1992, 48, 5667.

(12) Data sets were collected with an Enraf-Nonius CAD4

diffractometer. Programs used: data collection EXPRESS

(Nonius B.V., 1994), data reduction MolEN (K. Fair, Enraf-

Nonius B.V., 1990), structure solution SHELXS-97

(Sheldrick, G. M. Acta Cryst. 1990, A46, 467), structure

refinement SHELXL-97 (G. M. Sheldrick, Universität

Göttingen, 1997), graphics MOPICT 3.2 (M. Brüggemann,

Universität Münster, 2001). Crystallographic data

(excluding structure factors) for the structures reported in

this paper have been deposited with the Cambridge

Crystallographic Data Centre as supplementary publication

CCDC 182787 and 182786. Copies of the data can be

obtained free of charge on application to The Director,

CCDC, 12 Union Road, CambridgeCB2 1EZ, UK [fax: int.

code +44(1223)336033, e-mail: deposit@ccdc.cam.ac.uk].

(13) Reviews: (a) Evans, D. A. Stereoselective Alkylation of

Chiral Metal Enolates: Asymmetric Synthesis, Vol. 3;

Morrison, J. D., Ed.; Academic Press: Orlando, 1984, 1–

110. (b) Fráter, G. Alkylation of Ester Enolates In

Stereoselective Synthesis (Houben-Weyl), Vol. E21a;

Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,

Eds.; Thieme: Stuttgart, 1995, 723–790.

Anal. Calcd for C₂₃H₂₈O₂(336.47): C, 82.10; H, 8.39. Found: C,

81.91; H, 8.11.

Acknowledgment

The work was supported by the Deutsche Forschungsgemeinschaft,

the Fonds der Chemischen Industrie, and the Bayer AG. Mustafa

Özlügedik and Jenny Reuber would like to thank the Graduierten-

kolleg ‘Hochreaktive Mehrfachbindungssysteme’ for the funding.

References

(1) Responsible for X-Ray crystal structure data.

(2) Reviews: (a) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed.

Engl. 1997, 36, 2282; Angew. Chem. 1997, 109, 2376.

(b) Hoppe, D.; Marr, F.; Brüggemann, M. In Organolithium

in Enantioselective Synthesis, Topics in Organometallic

Chemistry, Vol. 5; Hodgson, D. M., Ed.; Springer-Verlag:

Berlin, 2003, 61. (c) Beak, P.; Johnson, T. A.; Kim, D. D. In

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(3) (a) Hoppe, D.; Zschage, O. Angew. Chem., Int. Ed. Engl.

1989, 28, 69; Angew. Chem. 1989, 101, 67. (b) Whisler, M.

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(14) Prasad, K. R.; Özlügedik, M.; Wibbeling, B.; Fröhlich, R.;

Hoppe, D., manuscript in preparation.

(15) Determined via the lactone derivative.

(4) Özlügedik, M.; Kristensen, J.; Wibbeling, B.; Fröhlich, R.;

Hoppe, D. Eur. J. Org. Chem. 2002, 414.

(5) Reviews on titanation: (a) Reetz, M. T. Organotitanium

Article Doi

Stereoselective synthesis of highly substituted bicyclic γ-lactones using homoaldol addition of 1-(1-cycloalkenyl)methyl carbamates

DOI: 10.1055/s-2004-831170

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