Stereochemical aspects of the Beckman rearrangement of oximes of levoglucosenone and its dihydro derivative. Enantioselective synthesis of (+)-γ-pelargonolactone

Article abstract of DOI:10.1023/B:CONC.0000018110.36123.f2

Regiospecific C⁵-halogenation with retention of configuration occurred upon Beckman fragmentation of levoglucosenone oxime using SOCl ₂ or PBr₃. On the other hand, the oxime of its dihydro derivative gave under these conditions the C⁶-substitution product. A stereoselective synthetic scheme for (+)-γ-pelargonolactone, an attractant for the rice and corn weevils Sitophiltus zeamais, was developed from the fragmentation product of levoglucosenone oxime.

Full text of DOI:10.1023/B:CONC.0000018110.36123.f2

Chemistry of Natural Compounds, Vol. 39, No. 6, 2003
STEREOCHEMICAL ASPECTS OF THE BECKMAN REARRANGEMENT
OF OXIMES OF LEVOGLUCOSENONE AND ITS DIHYDRO DERIVATIVE.
ENANTIOSELECTIVE SYNTHESIS OF (+)- -PELARGONOLACTONE
F. A. Valeev,1 E. V. Gorobets,1 I. P. Tsypysheva,1
G. Sh. Singizova,1 L. Kh. Kalimullina,2 M. G. Safarov,2
O. V. Shitikova,1 and M. S. Miftakhov1
UDC 547.917
5
Regiospecific C -halogenation with retention of configuration occurred upon Beckman fragmentation of
levoglucosenone oxime using SOCl or PBr . On the other hand, the oxime of its dihydro derivative
2
6
3
gave under these conditions the C - substitution product. A stereoselective synthetic scheme for
(+)-γ-pelargonolactone, an attractant for the rice and corn weevils Sitophiltus zeamais, was developed from
the fragmentation product of levoglucosenone oxime.
Key words: levoglucosenone, second-order Beckman rearrangement, ketoximes, nitriles, nucleophilic substitution.
The great synthetic potential of levoglucosenone as a platform compound has been demonstrated repeatedly in the
synthesis of complicated natural compounds [1]. The preparation of linear chiral chains using traditional methods is
problematic for carbohydrate chemistryin the case oflevoglucosenone. A promising approach tothe synthesis ofpolyfunctional
acyclic chiral moiety from levoglucosenone is Beckman fragmentation of levoglucosenone oxime, which is known to form
nitriles in the case of α-aminoketoximes, their ethers, α-aldoximes, α-halo-, -hydroxy-, -oxo-, and -carboxyketoximes [2].
We studied the fragmentation of levoglucosenone oxime 1 and its dihydro derivative 2 and devised a synthesis
of (+)-γ-pelargonolactone 15, an attractant of rice and corn weevils Sitophiltus zeamais, in order to prove the configuration of
the asymmetric center in the fragmentation product of 1.
The oxime of 1 was prepared using NH OH·HCl in pyridine as a mixture of the syn- and anti-isomers 3a and b in a
2
3:2 ratio. It should be noted that our attempts to carry out this reaction in MeONa—MeOH, KOH—EtOH, Et N,
3
K CO —MeOH, and EtOH—Py formed the known aldol-cleavage products [2]. Pure oximes 3a and b give rather quickly an
2
3
equilibrium mixture of the same ratio upon storage.
Second-order Beckman rearrangement was performed using SOCl and PBr in CCl . Both the pure isomers and their
2
3
4
mixture were reacted. This had no effect on the yields of nitriles 4 and 5. Subsequent acid hydrolysis of 4 formed the
functionally saturated chiral moiety 6 (Scheme 1).
The effect of the double bond on the rearrangement mechanism was evaluated by hydrogenating 1 over Pd/C (5%) to
13
afford 2. Formation of the oxime of 2 gave pure crystalline 8. The structure of oxime 8 was established using C NMR of the
starting ketones and their oximes. Like oxime 3a, C-3 of oxime 8 experiences a stronger coupling with the hydroxyl, shifting
from 30.57 ppm in the starting dihydrolevoglucosenone to 27.41 ppm in the oxime.
The rearrangement occurs with predominant formation of nitrile 9a upon reaction of oxime 8 with SOCl (Scheme 1).
2
13
The C atoms bound to Cl in chloroformates 4 and 9 resonate in the C NMR spectra taken in JMOD mode at 53.21
and 44.38 ppm, respectively, with a negative amplitude in the first instance (CH group); positive, in the second (CH group).
2
1) Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, pr. Oktyabrya,
71, fax (3472) 35 60 66, e-mail: chemorg@anrb.ru; 2) Bashkir State University, 450074, Ufa, ul. Frunze, 32. Translated from
Khimiya Prirodnykh Soedinenii, No. 6, pp. 465-469, November-December, 2003. Original article submitted September 25,
2003.
0009-3130/03/3906-0563$25.00 ©2003 Plenum Publishing Corporation
563

O
N
OCHO
OH
Cl
H
H
H
O
H
O
O
X
Cl
d
b
or c
e
CN
CN
CN
OH
3a (anti) : 3b (syn), 3 : 2
4: X = Cl;
5: X = Br
6
7
a
O
N
OCHO
Cl
H
H
O
H
O
Cl
OCHO
O
a
b
+
CN
CN
X
O
HO
1: X = -CH=CH-
2: X = -CH -CH -
8
9a : 9b, 9 : 1
2
2
a. NH OH HCl, Py; b. SOCl , CCl ; c. PBr , CCl ; d. HCl-THF; e. DHF, CH Cl , p-TsOH
2
2
4
3
4
2
2
Scheme 1.
Ring opening is stereospecific in both instances. Protection of the hydroxyl with tetrahydrofuran gives only two
diastereomers. The PMR spectrum using Eu(camph) shift reagent also unambiguously indicates the presence of one
3
enantiomer.
1
2
The proposed fragmentation mechanism consists ofthe cleavage ofthe C –C bond and S i substitution with retention
of configuration at C :
N
5
O
N
−
O
Cl
Cl
OCHO
Cl
O
H
O
O
CN
CN
S
O
Cl
4
An attempt to prove the configuration of the asymmetric center of 4 by oxidative hydrolysis and cyclization into the
known ( )-(-)-5-(hydroxymethyl)-2(5H)-furan [3] was unsuccessful. Mixtures of epimeric ethoxyoxiranes 10 formed.
S
Hydrolysis of 4 under phase-transfer-catalysis conditions also gave only a mixture of the - and
-isomeric epoxides 11a
trans
cis
and -b (85%). Storing 4 in pyridine gave diene 12 [4].
The configuration of the asymmetric center in the rearrangement product of the oxime of 4 was proved bysynthesizing
(+)-4( )-pentyl-γ-lactone 15, an attractant of the rice and corn weevils [5].
R
Sitophiltus zeamais
Known schemes for synthesizing optically active γ-lactones for introducing chiral centers use L-glutamic acid or
D-ribose [5]. One of the successful methods for forming the side chain in γ-lactones is based on regioselective opening of an
oxirane ring using a cuprate reagent [6]. We used this method in the developed synthesis. Thus, opening of the oxirane ring
in 11a and -b by butylcuprate reagent occurs regiospecifically to afford 13. Hydrogenation of the double bond with subsequent
20
hydrolysis of the cyano group and work up with aqueous HCl (10%) gave the target lactone 15 (72%) with [α]
+28.8° ( 1.0,
c
D
MeOH).
20
The sign of the optical rotation angle of 15 agrees with the literature value {lit. [α]
+47.2° ( 1.0, MeOH) [5]}.
c
D
Taking into account the inversion of configuration in preparing the oxirane, the configuration of the C-4 asymmetric center in
the fragmentation products of levoglucosenone (4 and 5) can be assigned to the -type. This confirms the proposed Beckman
S
fragmentation mechanism. The difference in the absolute value of the optical rotation angle is probably due to partial
racemization in the early steps.
564

OCHO
Cl
O
a
H
H
Cl
c
EtO
CN
CN
CN
b
4
10
12
OH
O
OH
O
H
d
e
f, g
O
CN
CN
11a (cis) : 11b (trans), 3 : 1
H
NC
13
14
15
a.
b.
c.
d.
e.
f.
t
g
H O - NaOH, EtOH; 50% KOH, CH Cl , TEBAC; Py; 1 eq. Bu CuLi; H -Pd/C; KOH, -BuOH; . 10% HCl
2
2
2
2
2
2
Scheme 2.
EXPERIMENTAL
13
IR spectra were recorded on UR-20 and Specord M-80 instruments (as films or in mineral oil). PMR and C NMR
spectra were recorded on an AM-300 (Bruker) spectrometer at working frequencies 300and 75.47 MHz, respectively, with TMS
internal standard and CDCl solvent. Analytical TLC was performed on Sorbfil plates (PTLC-AF-A grade, ZAO
3
"Sorbpolymer," Krasnodar). Optical rotation angles were measured on a Perkin—Elmer-141 instrument. Mass spectra were
measured in an MX-1306 instrument (ionization potential 70 eV, ionization-chamber temperature 30-50°C).
Analytical data for all compounds agreed with those calculated.
13
1,6-Anhydro-β-D-glycerohexopyranos-2-ulose (2)
was prepared as before [6]. C NMR (δ , ppm): 29.33 (C-4),
C
30.57 (C-3), 66.99 (C-6), 72.68 (C-5), 100.99 (C-1), 200.08 (C-2).
Syn- and anti-oximes of 1,6-anhydro-3,4-dideoxy-β-D-glycerohex-3-enopyranos-2-ulose (3a and b). A solution
of 1 (1.8 g) in pyridine (20 mL) was stirred and treated with NH OH·HCl (2.2 g). After 30 min the reaction mixture was treated
2
with ethylacetate (50 mL), washed with water (2 × 50 mL), dried over Na SO , filtered, and evaporated. The solid was
2
4
chromatographed over silica gel. Yield 1.8 g (92%) of
- and
-isomers of oximes (3a and b) in a 3:2 ratio (PMR). 0.38
anti R
f
syn
20
-1
(benzene—isopropanol, 9:1). C H O N, [α]
-54.5°( 1.0, CHCl ). IRspectrum (ν, cm ): 840, 910, 1000, 1130, 1270, 1300,
c
3
6
7
3
D
1460, 1660, 1720, 1740, 2920, 3100, 3400.
3a. PMR (δ, ppm, J/Hz): 3.85 (2H, m, H-6), 4.87 (1H, dtt, J = 4.8, 1.6, H-5), 5.73 (1H, d, J = 1.6, H-1), 6.60 (1H, dd,
J = 10.0, 4.8, H-4), 6.80 (1H, dd, J = 10.0, 1.6, H-3), 8.40-8.60 (1H, m, OH).
13
C NMR (δ , ppm): 70.22 (C-6), 72.10 (C-5), 100.09 (C-1), 115.57 (C-3), 137.90 (C-4), 150.06 (C-2).
C
3b. PMR (δ, ppm, J/Hz): 3.85 (1H, d, J = 6.6, H -6), 3.89 (1H, dd, J = 6.6, 4.8, H -6), 4.90 (1H, dt, J = 4.8, 1.6, H-5),
a
b
6.15 (1H, dd, J = 9.8, 1.6, H-3), 6.53 (1H, dd, J = 9.8, 4.8, H-4), 6.60 (1H, d, J = 1.6, H-1), 8.50-8.80 (1H, m, OH).
13
C NMR (δ , ppm): 69.09 (C-6), 71.35 (C-5), 93.07 (C-1), 122.30 (C-3), 135.70 (C-4), 152.60 (C-2).
C
4(S)-Chloro-5-formyloxypent-2-enonitrile (4). A cooled (0°C) solution of oxime 3 (1.9 g) in CCl (10 mL) was
4
treated dropwise with SOCl (1.2 mL) in CCl (10 mL), stirred at 0°C for 1 h, treated with saturated aqueous NaCl solution
2
4
(20 mL), and extracted with CCl (3 × 20 mL). The combined organic layers were dried over MgSO and evaporated to
4
4
20
-1
afford 4 (1.4 g, 65%), C H O NCl. 0.3 (heptane—ethylacetate, 1:1). [α]
+116.9° ( 1.0, CHCl ). IR spectrum (ν, cm ):
c
3
R
6
6
2
f
D
740, 830, 1160, 1650, 1740, 2220, 2950.
PMR (δ, ppm, J/Hz): 4.41 (1H, dd, J = 5.6, 1.6, H -5), 4.45 (1H, dd, J = 11.6, 6.7, H -5), 5.0 (1H, ddd, J = 10.2, 6.7,
a
b
5.6, H-4), 5.51 (1H, d, J = 10.9, H-2), 6.51 (1H, dd, J = 10.9, 10.2, H-3), 8.10 (s, 1H, –OCHO).
13
C NMR (δ , ppm): 53.21 (C-4), 64.47 (C-5), 103.27 (C-2), 113.98 (CN), 147.56 (C-3), 159.76 (–OCHO).
C
4(S)-Bromo-5-formyloxypent-2-enonitrile (5). A cooled (0°C) solution of oxime 3 (1.0 g) in CCl (10 mL) was
4
treated dropwise with PBr (1.2 g) in CCl (10 mL), stirred at 0°C for 2 h, treated with saturated aqueous NaCl solution
3
4
565

(20 mL), and extracted with CCl (3 × 20 mL). The combined organic layers were dried over MgSO and evaporated to afford
4
-1
5 (1.1 g, 70%), C H O NBr. IR spectrum (ν, cm ): 680, 830, 1150, 1650, 1740, 2210, 2960.
6
6 2
PMR (δ, ppm, J/Hz): 4.42 (1H, dd, J = 11.6, 7.6, H -5), 4.48 (1H, dd, J = 11.6, 5.5, H -5), 5.0 (1H, ddd, J = 10.6, 7.6,
a
b
5.5, H-4), 5.47 (1H, d, J = 10.9, H-2), 5.5 (1H, dd, J = 10.9, 10.6, H-3), 8.03 (1H, s, –OCHO).
13
C NMR (δ , ppm): 42.18 (C-4), 64.65 (C-5), 102.54 (C-2), 114.02 (CN), 148.09 (C-3), 159.70 (–OCHO).
C
4(S)-Chloro-5-hydroxypent-2-enonitrile (6). A solution of 4 (0.5 g) in THF was treated with aqueous HCl (5 mL,
5%) and stirred at room temperature for 1 h. The reaction mixture was neutralized by NaHCO solution and extracted with
3
ethylacetate (3 × 30 mL). The combined organic layers were dried over MgSO , evaporated, and chromatographed over SiO
4
20
2
-1
toafford 6(0.3g, 73.5%), C H ONCl. R 0.5 (benzene—isopropanol, 9:1). [α]
+23.3° (c 1.0, CHCl ). IRspectrum (ν, cm ):
3
f
5
6
D
740, 790, 830, 1060, 1100, 1645, 1740, 2250, 2900, 2970, 3090, 3450.
PMR (δ, ppm, J/Hz): 3.58 (1H, br.s, OH), 3.72 (1H, dd, J = 11.9, 5.6, H -5), 3.80 (1H, dd, J = 11.9, 5.5, H -5), 4.75
a
b
(1H, ddd, J = 11.0, 5.6, 5.5, H-4), 5.50 (1H, d, J = 10.8, H-2), 6.48 (1H, dd, J = 11.0, 10.8, H-3).
13
C NMR (δ , ppm): 57.69 (C-4), 65.15 (C-5), 102.25 (C-2), 114.45 (C-1), 149.34 (C-3). Mass spectrum (EI, m/z,
C
+
+
+
+
+
I , %): [M] not observed, 103, 101 (25) [M - CH OH] , 52 (37) [CH =CH–CN] , 39 (65) [C H ] , 31 (100) [CH =OH] .
rel
2
2
3
3
2
4(S)-Chloro-5-tetrahydrofuranyloxypent-2-enonitrile (7a and b). A cooled (0°C) solution of6 (0.127 g) in CH Cl
2
2
(5 mL) was treated with DHF (0.22 mL) and stirred at room temperature for 3 h with catalytic amounts of p-TsOH. After the
starting material disappeared (TLC monitoring), the mixture was washed with water, dried over MgSO , and concentrated.
4
Column chromatography isolated a diastereomeric mixture (55:45) of 7a and b (0.108 g), C H O NCl, R 0.64
f
9
12 2
(hexane—ethylacetate, 3:1) in 56% yield.
PMR (δ, ppm, J/Hz): 7a, 1.62-1.88 (4H, m, H -2′, H -3′), 3.50-3.81 (4H, m, H -5, H -4′), 4.75 (1H, m, H-4), 5.03 (1H,
2
2
2
2
m, H-1′), 5.43 (1H, d, J = 10.5, H-2), 6.38 (1H, dd, J = 10.5, 3.6, H-3). 7b, 1.62-1.88 (4H, m, H -2′, H -3′), 3.50-3.81 (4H, m,
2
2
H -5, H -4′), 4.75 (1H, m, H-4), 5.03 (1H, m, H-1′), 5.42 (1H, d, J = 10.6, H-2), 6.34 (1H, dd, J = 10.5, 3.6, H-3).
2
2
13
C NMR (δ, ppm): 7a, 22.48 (C-3′), 31.8 (C-2′), 54.6 (C-4), 68.61 (C-4′), 67.05 (C-5), 101.8 (C-2), 104.31 (C-1′),
114.18 (C-1), 149.36 (C-3). 7b, 22.94 (C-3′), 31.95 (C-2′), 54.68 (C-4), 66.83 (C-4 ), 69.49 (C-5), 101.94 (C-2′), 103.42 (C-1′),
114.18 (C-1), 149.51 (C-3).
1,6-Anhydro-β-D-glycerohexopyranos-2-ulose oxime (8). A solution of 2 (3.9 g) in Py (50 mL) was stirred and
treated with NH OH·HCl (4.9 g) (TLC monitoring). After 30 min the reaction mixture was diluted with ethylacetate (130 mL),
2
washed with water (2 × 130), dried over MgSO , and evaporated. The solid was chromatographed over silica gel to afford 8
4
20
(2.51 g, 57.7%), C H O N, R 0.3 (heptane—ethylacetate, 4:1), [α]
-100.5° (c 1.0, CHCl ).
3
f
6
9
3
D
eq
ax
PMR (δ, ppm, J/Hz): 1.75 (1H, ddd, J = 13.8, 8.0, 0.8, H -4), 2.05 (1H, dddd, J = 13.8, 11.4, 7.2, 3.5, H -4), 2.25
(1H, ddd, J = 16.8, 11.4, 3.4, H -3), 3.05 (1H, ddd, J = 16.8, 7.2, 1.0, H -3), 3.87 (1H, dd, J = 7.1, 5.3, H-6), 3.93 (1H, d,
J = 7.1, H-6), 4.67 (1H, br.s, H-5), 5.51 (1H, s, H-1), 8.85 (1H, s, OH).
ax
eq
13
C NMR (δ , ppm): 15.86 (C-4), 27.41 (C-3), 67.15 (C-6), 73.16 (C-5), 100.08 (C-1), 153.95 (C-2).
C
5(S)-Chloro-4-formyloxypentonitrile (9a and b). A cooled (0°C) solution of the oxime (2.3 g) in CCl (12 mL) was
4
treated dropwise with SOCl (1.45 mL) in CCl (12 mL), stirred at 0°C for 1 h (TLC monitoring), treated with saturated
2
4
aqueous NaCl solution (25 mL), and extracted with CCl (3 × 25 mL). The combined organic layers were dried over MgSO
4
4
20
and evaporated to afford 9a and b (1.7 g, 65.4%), C H O NCl, R 0.3 (heptane—ethylacetate, 5:1), [α]
D
-28.2° (c 1.0,
f
6
8
2
CHCl ).
3
PMR (δ, ppm, J/Hz): 9a, 2.0 (2H, dt, J = 7.3, 6.4, 2H-3), 2.36 (2H, t, J = 7.3, 2H-2), 3.53 (1H, dd, J = 11.9, 4.7, H -6),
a
3.60 (1H, dd, J = 11.9, 5.0, H -6), 5.12 (1H, ddt, J = 6.4, 5.0, 4.7, H-5), 8.05 (1H, s, –OCHO). 9b, 2.15 (2H, m, 2H-3), 2.6 (2H,
b
m, 2H-2), 4.1 (1H, m, H-4), 4.28 (2H, m, 2H-5), 8.03 (1H, s, –OCHO).
13
C NMR (δ , ppm): 9a, 12.94 (C-2), 26.79 (C-3), 44.38 (C-5), 70.32 (C-4), 118.50 (CN), 159.95 (–OCHO). 9b, 14.01
C
(C-2), 29.73 (C-3), 56.51 (C-4), 59.86 (C-5), 118.50 (CN), 159.95 (–OCHO).
(1′R)-Oxiranyl-3-ethoxypropanonitrile (10). A solution of 6 (0.5 g, 3.8 mmol) in ethanol (7 mL) was treated with
KOH solution (6.8 mL, 30%) and slowlydropwise with H O (1.9 mL, 30%), heated to 80°C, and held at that temperature until
2
2
the reaction was complete (TLC monitoring). The temperature was lowered to 55°C. The solution was treated slowly with
finelyground KOH until the foaming stopped. The solution was acidified with HCl (6%) until the pH was 3 and extracted with
ethylacetate (3 × 10 mL). The organic layers were combined, dried over Na SO , filtered, and evaporated. The solid was
2
4
chromatographed over SiO using hexane—ethylacetate (1:1) to afford 10 (0.42 g, 78%), C H O N.
2
7 11 2
566

13
C NMR (δ, ppm): 14.94, 15.00 (CH ), 20.89, 21.41 (C-1), 43.22, 45.87 (C-2′), 51.74, 52.98 (C-3), 65.88, 65.96
3
(CH O), 74.47, 75.48 (C-2), 116.79, 116.90 (CN).
2
(1′R)-3-Oxiranylprop-2(Z,E)-enonitriles (11a and b). A cooled (0°C) solution of 6 (1.2 g, 9.16 mmol) in CH Cl
2
2
(10 mL) was vigorously stirred with catalyatic amounts of TEBAC, treated slowly dropwise with KOH solution (3 mL,
10.1 mmol, 50%) (TLC monitoring), diluted with water (10 mL), and extracted with CH Cl (3 × 5 mL). The organic layers
2
2
were combined, dried over Na SO , and evaporated. Column chromatography over SiO (hexane—ethylacetate, 1:1)
2
4
2
afforded (R = 0.3) 11a and -b (0.671 g, 85%, 3:1 ratio), C H ON.
f
5
5
PMR (δ, ppm, J/Hz): Syn-isomer 11a, 2.80 (1H, dd, J = 5.4, 2.3, H -2′), 3.10 (1H, dd, J = 5.4, 4.3, H -2′), 3.82 (1H,
a
b
ddd, J = 8.9, 4.3, 2.4, H-3), 5.60 (1H, d, J = 11.4, H-1), 6.08 (1H, dd, J = 11.4, 8.9, H-2).
13
C NMR (δ, ppm): 48.24 (C-2′), 49.51 (C-3), 103.21 (C-1), 114.96 (CN), 151.13 (C-2). Anti-isomer 11b, 2.70 (1H,
dd, J = 5.5, 2.5, H -2′), 3.05 (1H, dd, J = 5.5, 4.3, H -2′), 3.45 (1H, ddd, J = 6.6, 4.3, 2.5, H-3), 5.70 (1H, d, J = 16.4, H-1), 6.50
a
b
13
(1H, dd, J = 16.4, 6.6, H-2). C NMR (δ, ppm): 49.80 (C-2′), 50.21 (C-3), 102.14 (C-1), 114.96 (CN), 151.04 (C-2).
(Z)-3-Chloro-1-cyanobuta-1,3-diene (12). A solution of4 (0.1 g) in pyridine (2 mL) was held at 20°C for 24 h, treated
with water (5 mL), and extracted with ethylacetate (3 × 3 mL). The organic layers were combined, washed with aqueous HCl
(10%), dried over MgSO , and evaporated. The solid was chromatographed over SiO to afford 12 (0.034 g, 86%). Spectral
4
2
data corresponded with those published previously [4].
4(R)-Hydroxynon-2-(E)-enonitrile (13). A suspension of CuI (0.480 g, 2.3 mmol) in absolute Et O was stirred
2
vigorously at -40°C, treated slowly dropwise with BuLi (1.74 mL, 4.58 mmol, 2.63 N), stirred at the same temperature for
30 min, cooled to -80°C, treated with a solution of 11 (0.200 g, 2.10 mmol) in ether (3 mL), and held at -80°C for 1 h. The
temperature was slowly raised to 0°C. The mixture was hydrolyzed with NH Cl solution. The organic layer was separated.
4
The aqueous layer was extracted with EtOAc (3 × 25 mL). The organic layers were combined and dried over MgSO . Column
4
20
chromatography over SiO (hexane—ethylacetate, 2:1) afforded 13 (0.079 g, 66%), C H ON, [α]
-21.4 (c 1.0, CHCl ).
3
2
9
15
D
PMR (δ, ppm, J/Hz): 0.90 (3H, t, J = 6.7, H-9), 1.23-1.40 (6H, m, 2H-6,7,8), 1.54 (1H, quint., J = 6.7, H -5), 1.545
a
(1H, quint., J = 6.7, H -5), 1.8 (1H, br.s, OH), 4.29 (1H, ddt, J = 6.7, 4.3, 2.0, H-4), 5.67 (1H, dd, J = 16.1, 2.0, H-2), 6.76 (1H,
b
dd, J = 16.1, 4.2, H-3).
13
C NMR ( , ppm): 13.88 (CH ), 22.41 (C-8), 24.69 (C-6), 31.48 (C-7), 36.27 (C-5), 70.87 (C-4), 98.48 (C-2), 117.37
3
(CN), 156.92 (C-3).
4(R)-Hydroxynononitrile (14). A solution of 13 (0.350 g, 2.3 mmol) in ethylacetate was treated with Pd/C (0.035 g,
5%) and stirred under a H atomsphere (TLC monitoring). After 36 h the reaction mixture was filtered and evaporated. The
2
20
solid was chromatographed over SiO (hexane—ethylacetate, 3:1) to afford 14 (0.339 g, 97%), C H ON, [α]
D
-18.3 (c 1.0,
2
9
17
CHCl ).
3
PMR (δ, ppm, J/Hz): 0.82 (3H, t, J = 6.3, H-9), 1.12-1.35 (4H, m, H -7, H -8), 1.38 (2H, m, H -6), 1.60 (2H, m, H -5),
2
2
2
2
1.6 (1H, m, OH), 1.61 (1H, quint., J = 6.7, H -5), 1.63 (1H, quint., J = 6.7, H -5), 1.75 (1H, ddt, J = 7.9, 7.6, 3.4, H -3), 1.80
a
b
a
(1H, ddt, J = 7.9, 7.6, 3.4, H -3), 2.44 (1H, t, J = 7.6, H -2), 2.45 (1H, t, J = 7.6, H -2), 3.65 (1H, ttt, J = 6.7, 3.4, H-4).
b
a
b
13
C NMR (δ, ppm): 13.68 (C-2), 13.98 (CH ), 22.52 (C-8), 25.12 (C-6), 31.62 (C-7), 32.46 (C-3), 37.42 (C-5), 70.0
3
(C-4), 119.95 (CN).
4(R)-Pentyl-γ-lactone (15). A solution of 14 (0.30 g, 1.93 mmol) dissolved in t-BuOH (3 mL) was treated with finely
ground KOH (0.38 g, 6.7 mmol), refluxed until the starting material disappeared (TLC monitoring), cooled to 0°C, diluted with
saturated NaCl solution (10 mL), stirred, treated with HCl (12 N) until the pH reached 5, and extracted with CHCl (3 × 5 mL).
3
The organic layers were combined, dried over MgSO , and evaporated. The solid was chromatographed over SiO to afford
4
2
20
15, (0.134 g, 72%), C H O , [α]
D
+28.8° (c 1.0, MeOH).
9
16
2
PMR (δ, ppm, J/Hz): 0.9 (3H, t, J = 6.5, 3H-5′), 1.35 (4H, m, 2H-4′ and 2H-3′), 1.45 (2H, m, 2H-2 ), 1.6 (1H, tdd,
J = 9.8, 7.4, 5.4, H -1′), 1.72 (1H, tdd, J = 9.8, 7.4, 5.4, H -1′), 1.85 (1H, tdd, J = 12.5, 9.6, 8.9, H -3), 2.35 (1H, ddd, J = 12.5,
a
b
a
6.7, 6.4, H -3), 2.55 (2H, dd, J = 9.6, 6.7, 2H-2), 4.5 (1H, dddd, J = 8.9, 7.4, 6.4, 5.2, H-4).
b
13
C NMR (δ, ppm): 13.96(C-5′), 22.50 (C-4′), 24.91 (C-2′), 28.02 (C-3), 28.89 (C-2), 31.51 (C-3′), 35.55 (C-1′), 81.18
(C-4), 177.4 (C-1).
567

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2.
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4.
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568