A concise enantioselective synthesis of (+)-decarestrictine L via proline-catalyzed sequential α-aminooxylation and Horner-Wadsworth-Emmons olefination

Article abstract of DOI:10.1016/j.tetasy.2009.08.026

A short enantioselective synthesis of (+)-decarestrictine L, a cholesterol biosynthesis inhibitor metabolite, is described using a d-proline catalyzed sequential α-aminooxylation and a Horner-Wadsworth-Emmons olefination.

Full text of DOI:10.1016/j.tetasy.2009.08.026

Tetrahedron: Asymmetry 20 (2009) 2173–2177
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A concise enantioselective synthesis of (+)-decarestrictine L via
proline-catalyzed sequential a-aminooxylation and
Horner–Wadsworth–Emmons olefination
*
Varun Rawat, Pandurang V. Chouthaiwale, Gurunath Suryavanshi, Arumugam Sudalai
Chemical Engineering and Process Development Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2009
Accepted 27 August 2009
Available online 25 September 2009
A short enantioselective synthesis of (+)-decarestrictine L, a cholesterol biosynthesis inhibitor metabolite,
is described using a
Emmons olefination.
D
-proline catalyzed sequential
a
-aminooxylation and a Horner–Wadsworth–
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The decarestrictines are secondary metabolites that were iso-
lated from various Penicillium strains.1 Several members of the
decarestrictine family of natural products have been shown to in-
hibit the biosynthesis of cholesterol in both a HEP-G2 liver cells as-
say and in vivo.2 While the majority of the decarestrictines contain
a 10-membered lactone ring in their structure,1–3 decarestrictine L
1 is unique in possessing a tetrahydropyranyl nucleus (Fig. 1).2
Decarestrictine L 1 was isolated as a minor component from a cul-
ture broth of Penicillium simplicissium in 19921 and its absolute
configuration (+)-(2R,3S,6R) was subsequently confirmed by total
synthesis by Kibayashi et al.4 Several other syntheses5 of decare-
strictine L 1 have been reported but many suffer from one or more
disadvantages, which include the use of chiral building blocks, long
reaction sequences, and low yields.6 In recent years, proline and its
derivatives have proven to be versatile organocatalysts.7 Herein,
we report an efficient synthesis of (+)-decarestrictine L 1 from
The retrosynthetic approach to (+)-decarestrictine L 1 is out-
lined in Scheme 1. Decarestrictine L 1 was envisioned to be ob-
tained via intramolecular cyclization involving 1,4-conjugate
addition of enone 2. We envisaged a D-proline-catalyzed sequential
aminooxylation–olefination of aldehyde 3 for the efficient con-
struction of enone moiety 2. Aldehyde 3, a suitable intermediate,
could be obtained by two routes: (i) Jacobsen’s hydrolytic kinetic
resolution (HKR)9 of terminal epoxide ( )-4 and (ii) Noyori’s asym-
metric reduction10 of b-ketoester 7.
Route 1 presents the synthesis of intermediate aldehyde 3
which commences with 5-hexene-1-ol 5, protected as its benzyl
ether 8. The olefinic function in 8 was epoxidized smoothly
{MCPBA, CHCl3} to give racemic epoxide ( )-4, which was sub-
jected to Jacobsen’s HKR9 {(S,S)-cobalt salen, H2O} to give the cor-
responding enantiomerically pure epoxide (ꢀ)-4 in 43% yield and
99% ee, {½a 2D5
¼ ꢀ5:1 (c 2.0, CHCl3)} along with the separable diol
ꢁ
the readily available raw materials via a
D
-proline-catalyzed
9 in 47% yield. The chiral epoxide (ꢀ)-4, readily purified by column
chromatography, was subjected to regioselective reductive ring
opening with LiAlH4 in THF at 0 °C to afford the secondary alcohol
10 as the exclusive product in 92% yield and 99% ee. The alcohol 10
was protected as its TBS ether (TBSCl, imid.) and the benzyl ether
11 were subsequently deprotected under hydrogenolysis condi-
tions {10% Pd/C, H2 (1 atm), Et3N} to give the primary alcohol 12
in 97% yield. The oxidation of alcohol 12 (IBX, DMSO) produced
sequential aminooxylation–olefination8 reaction followed by intra-
molecular conjugate 1,4-addition as the key reactions (Scheme 4).
OH
O
the key intermediate aldehyde 3 in 98% yield {½a D25
¼ ꢀ12:0 (c
ꢁ
O
3.0, CHCl3)} (Scheme 2). Since the overall yield that could be real-
ized for intermediate aldehyde 3 in HKR route was considerably
lower (30%), we envisioned an alternate route for its synthesis.
Noyori’s discovery of rhodium(I) and ruthenium(II) complexes
of BINAP enantiomers has revolutionized stereoselective organic
synthesis.10a In particular, stereo- and chemoselective reduction
of b-ketoesters to the corresponding b-hydroxyesters can be
1
Figure 1.
* Corresponding author. Tel.: +91 20 25902174; fax: +91 20 25902676.
E-mail address: a.sudalai@ncl.res.in (A. Sudalai).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.026

2174
V. Rawat et al. / Tetrahedron: Asymmetry 20 (2009) 2173–2177
OH
OR O
O
O
TBSO
O
iii
i
OEt
OEt
H
O
O
13, R = H
15
iv
7
ii
O
1
14, R = TBS
OTBS
O
OTBS
OTBS
v
CHO
OEt
ONHPh
2
6
3
Scheme 3. Reagents and conditions: (i) [(R)-Ru(BINAP)Cl2]2ꢂNEt3 (0.1 mol %), 2 M
HCl (0.1 mol %), MeOH, H2 (100 psi), 50 °C, 16 h, 95%, 98% ee; (ii) TBSCl, imid.,
CH2Cl2, 0–25 °C, 2 h, 97%; (iii) DIBAL-H, toluene, ꢀ78 °C, 1 h, 85%; (iv)
Ph3P@CHCO2Et, THF, 25 °C, 12 h, 93%; (v) (a) H2 (1 atm), 10% Pd/C,Et3N, MeOH,
12 h; (b) DIBAL-H, toluene, ꢀ78 °C, 1 h, 82% (for two steps).
OTBS
CHO
produced (R)-ethyl 3-hydroxybutyrate11 13 in 95% yield with high
enantiopurity (98% ee, Mosher ester). After protecting as its TBS
ether, the resulting ester 14 was subjected to selective reduction
with DIBAL-H at ꢀ78 °C that afforded the corresponding aldehyde
15 in 85% yield which was immediately reacted with the stabilized
3
route 1
route 2
OTBS
O
O
OBn
OH
OEt
Wittig salt to give
a,b-unsaturated ester 6 in 93% yield,
4
(-)-
6
{½a 2D5
¼ ꢀ15:8 (c 2.4, CHCl3)}. Exposure of the ester 6 to 10% Pd/C
ꢁ
under H2 (1 atm) followed by its selective reduction with DIBAL-
H at ꢀ78 °C furnished aldehyde 3 in 60% overall yield (Scheme 3).
With the intermediate aldehyde 3 readily available, we carried
out the sequential aminoxylation–olefination on aldehyde 3 cata-
O
O
lyzed by
D
-proline at ꢀ20 °C, that resulted in the formation of the
OEt
precursor aminooxy olefinic ketone 2 in 60% yield. The final step
was the TBAF-mediated deprotection of TBS ether in 2, which
should result in simultaneous cyclization to produce tetrahydro-
pyranyl skeleton 1. Unfortunately, the desired 1,4-conjugate addi-
tion did not proceed to give the desired product even after the use
of several Lewis acids (e.g., BF3ꢂOEt2, Cu(OTf)2, CuI or AuCl3). In
turn, the reaction produced complex mixtures, which were difficult
to separate. However, the removal of anilinoxy group in 2,
{Cu(OAc)2, EtOH},8f followed by desilylation (TBAF, THF) of the
5
7
Scheme 1. Retrosynthetic route to decarestrictine L.
achieved in high yields and excellent enantioselectivity.10b Our
second approach toward the synthesis of intermediate aldehyde
3 involves Ru-catalyzed asymmetric reduction10c {[(R)-Ru(BIN-
AP)Cl2]2ꢂNEt3, 2 N HCl, H2 (100 psi)} of ethyl acetoacetate 7 that
OH
HO
OBn
9
O
ii
iii
OR
OBn
O
5, R = H
(
)- 4
i
OBn
8, R =Bn
(-)- 4
iv
OR
vii
OTBS
CHO
OR1
10, R = H ; R1 = Bn
3
v
11, R = TBS ; R1 = Bn
12, R = TBS ; R1 = H
vi
Scheme 2. Reagents and conditions: (i) BnBr, NaH, THF, 0–25 °C, 6 h, 97%; (ii) MCPBA, CHCl3, 25 °C, 6 h, 85%; (iii) (S,S)-(–)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-
cyclohexanediaminocobalt (0.5 mol %), H2O (0.55 equiv), 24 h, 43%, 99% ee; (iv) LiAlH4, THF, 0 °C, 30 min, 92%, 99% ee; (v) TBSCl, Imid., CH2Cl2, 0–25 °C, 2 h, 98%; (vi) H2
(1 atm), 10% Pd/C, Et3N, MeOH, 12 h, 25 °C, 97%; (vii) IBX, DMSO, 25 °C. 2 h, 98%.

V. Rawat et al. / Tetrahedron: Asymmetry 20 (2009) 2173–2177
2175
OH
OTBS
O
O
OTBS
ii
i
CHO
O
ONHPh
1
2
3
Scheme 4. Reagents and conditions: (i) PhNO (0.9 equiv),
ꢀ20 to 0 °C, 2 h, 60%; (ii) (a) Cu(OAc)2, EtOH, 25 °C, overnight; (b) TBAF, THF, 25 °C, 6 h, 60% (over two steps).
D
-proline (20 mol %), ꢀ20 °C, 24 h then diethyl (2-oxopropyl)phosphonate (1.5 equiv), cesium carbonate (1.5 equiv),
crude product induced an instantaneous intramolecular 1,4-conju-
gate addition4,5a to afford (+)-decarestrictine L 1 in 60% yield over
two steps. The synthetic (+)-decarestrictine L 1 was identical in all
respects to the natural product.
moved under reduced pressure and the residue was extracted with
ethylacetate. The organic layer was washed with saturated NaH-
CO3 solution, brine, and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure to afford the crude product
which was subjected to column chromatographic purification with
petroleum ether/ethyl acetate (19:1 v/v) to give the racemic epox-
ide ( )-4 as a colorless liquid. Yield: 16.59 g, 85% yield; IR (CHCl3,
cmꢀ1) 3032, 2859, 1637, 1496, 1454, 1410, 1362; 1H NMR
(200 MHz, CDCl3): d 7.26–7.33 (m, 5H), 4.48 (s, 2H), 3.46 (t,
J = 6.0 Hz, 2H), 2.86–2.88 (m, 1H), 2.69 (dd, J = 4.0, 5.1 Hz, 1H),
2.43 (dd, J = 2.8, 5.2 Hz, 1H), 1.51–1.66 (m, 6H); 13C NMR
(50 MHz, CDCl3): d 138.6, 128.3, 127.6, 127.5, 72.9, 70.1, 52.1,
46.9, 32.3, 29.6, 22.8. Anal. Calcd for C13H18O2: C, 75.69; H, 8.80.
Found: C, 75.67; H, 8.80.
3. Conclusion
In conclusion, we have demonstrated the use of
D-proline cata-
lyzed sequential -aminooxylation–olefination strategy for the
a
concise synthesis of (+)-decarestrictine L 1 with an overall yield
of 22% (route 2). Simple procedures, easy to use reagents, cheap,
and readily available starting materials are some of the salient fea-
tures of this approach.
4. Experimental section
4.1. General information
4.4. (S)-2-[4-(Benzyloxy)butyl]oxirane, (ꢀ)-4
To a suspension of (S,S)-(ꢀ)-N,N-bis(3,5-di-tert-butylsalicylid-
ene)-1,2-cyclohexane-diaminocobalt (190 mg, 0.5 mol%) in toluene
(2 mL) was added acetic acid (0.026 mL, 0.1 mol %) and the mixture
was stirred while open to air for 1 h at 25 °C. The solvent was then
removed under reduced pressure and the brown residue was dried
under vacuum. The racemic epoxide ( )-4 (13.0 g, 63.10 mmol)
was added in one portion and the reaction mixture was then cooled
in an ice bath. Water (0.55 equiv 0.64 mL) was added slowly, fol-
lowed by stirring at 25 °C for 24 h. After completion of reaction
(monitored by TLC), the reaction mixture was subjected to column
chromatographic purification with petroleum ether/ethyl acetate
(19:1 v/v) to afford the (S)-epoxide (ꢀ)-4 in 43% yield (5.60 g);
Solvents were purified and dried by standard procedures before
use. Optical rotations were measured using sodium D line on a JAS-
CO-181 digital polarimeter. 1H NMR and 13C NMR spectra were re-
corded on Brucker AC-200 spectrometer unless mentioned
otherwise. Elemental analysis was carried out on a Carlo Erba
CHNS-O analyzer. IR spectra were recorded on a Perkin–Elmer
model 683 B and absorption is expressed in cmꢀ1. Purification
was done using column chromatography (60–120 mesh).
4.2. 1-Benzyloxy-hex-5-ene, 8
½
a 2D5
ꢁ
¼ ꢀ5:1 (c 2.0, CHCl3); 99% ee (HPLC). HPLC analysis: Column:
To a stirred suspension of activated NaH (2.88 g, 119.81 mmol)
in dry THF (100 mL)
a solution of 5-hexen-1-ol 5 (10.0 g,
LichrocartÒ (250 ꢃ 4.6 mm), Merck 5
lm, mobile phase: isopropyl-
alcohol/n-hexane (2/98), wavelength: 254 nm, flow rate: 1.0 mL/
99.84 mmol) in dry THF (100 mL) was added dropwise at 0 °C fol-
lowed by the addition of benzyl bromide (20.49 g, 119.81 mmol).
The reaction mixture was then stirred at 25 °C for 6 h. After the
completion of reaction (monitored by TLC), it was quenched with
saturated solution of ammonium chloride and the product was ex-
tracted with diethyl ether. The combined organic layer was then
washed with water, brine, and dried over anhydrous Na2SO4. Re-
moval of solvent under reduced pressure and column chromato-
graphic purification with petroleum ether/ethyl acetate (49:1 v/
v) gave the benzyl ether 8 as a colorless liquid. Yield: 18.43 g,
97% yield; IR (CHCl3, cmꢀ1) 3065, 3030, 2976, 2857, 1640, 1496,
1454; 1H NMR (200 MHz, CDCl3): d 7.29–7.32 (m, 5H), 5.78–5.86
(m, 1H), 4.97–5.10 (m, 2H), 4.54 (s, 2H), 3.51 (t, J = 6.2 Hz, 2H),
2.00 (q, J = 7.1 Hz, 2H), 1.38–1.70 (m, 4H); 13C NMR (50 MHz,
CDCl3): d 138.8, 138.6, 128.4, 127.6, 127.5, 114.7, 72.9, 70.3, 33.7,
29.4, and 25.6. Anal. Calcd for C13H18O: C, 82.06; H, 9.53. Found:
C, 82.08; H, 9.55.
min, retention time: 2.65 min (ꢀ)-isomer, 3.23 min (+)-isomer.
4.5. (R)-6-(Benzyloxy)hexan-2-ol, 10
To a suspension of LiAlH4 (1.01 g, 26.66 mmol) in dry THF
(30 mL), a solution of epoxide (ꢀ)-4 (5.0 g, 24.24 mmol) in THF
(50 mL) was added dropwise at 0 °C. The reaction mixture was stir-
red at this temperature for 30 min. After completion of reaction
(monitored by TLC), it was quenched with aq 20% solution of sodium
hydroxide (2 mL) at 0 °C. The reaction mixture was filtered through
sintered funnel, dried over anhydrous Na2SO4 and concentrated.
Purification by column chromatography with petroleum ether/ethyl
acetate (9:1 v/v) gave the secondary alcohol 10 as a colorless liquid.
Yield: 4.65 g (92%); ½a D25
¼ ꢀ7:9 (c 2.0, CHCl3); 99% ee (HPLC); IR
ꢁ
(neat, cmꢀ1): 3354, 2935, 1657, 1460, 1416, 1375, 1300; 1H NMR
(200 MHz, CDCl3): d 7.29–7.33 (m, 5H), 4.48 (s, 2H), 3.70–3.79 (m,
1H), 3.46 (t, J = 6.2 Hz, 2H), 2.0 (br s, 1H), 1.41–1.70 (m, 6H), 1.15
(d, J = 6.2 Hz, 3H); 13C NMR (50 MHz, CDCl3): d 138.5, 128.3, 127.6,
127.5, 72.9, 70.3, 67.6, 39.0, 29.7, 23.5, 22.4. Anal. Calcd for
C13H20O2: C, 74.96; H, 9.68. Found: C, 75.75; H, 9.66. HPLC analysis:
4.3. 2-[4-(Benzyloxy)butyl]oxirane ( )-4
To a stirred solution of olefin 8 (18.0 g, 94.60 mmol) in dry
CHCl3 (350 mL) was added m-chloroperbenzoic acid (48.97 g,
283.80 mmol) and the mixture was stirred at 25 °C for 6 h. After
completion of reaction (monitored by TLC), the solvent was re-
Column: LichrocartÒ (250 ꢃ 4.6 mm), Merck 5
lm, mobile phase:
isopropylalcohol/n-hexane (1/99), wavelength: 254 nm, flow rate:

2176
V. Rawat et al. / Tetrahedron: Asymmetry 20 (2009) 2173–2177
1.0 mL/min, retention time: 2.94 min (+)-isomer, 5.63 min (ꢀ)-
by evacuating and refilling with hydrogen several times. The appa-
ratus was heated at 50 °C with stirring under 100 psi of hydrogen
for 16 h. After completion of reaction (monitored by TLC) the reac-
tion was cooled and concentrated under reduced pressure. The res-
idue was subjected to column chromatographic purification with
petroleum ether/ethyl acetate (9:1 v/v) to get pure (R)-alcohol 13
isomer.
4.6. (R)-[6-(Benzyloxy)hexan-2-yloxy]-tert-
butyldimethylsilane, 11
To a solution of alcohol 10 (4.50 g, 21.60 mmol) in dry CH2Cl2
(80 mL) at 0 °C were added imidazole (2.94 g, 43.20 mmol) and
tert-butyldimethylsilyl chloride (4.88 g, 32.40 mmol). The reaction
mixture was then stirred at 25 °C for 2 h. After completion of reac-
tion (monitored by TLC), it was diluted with CH2Cl2, washed with
water, brine, and dried over anhydrous Na2SO4. Removal of the sol-
vent under reduced pressure gave the crude product which was
then purified by column chromatography with pure petroleum
as a colorless liquid. Yield: 7.23 g, (95%); ½a D25
¼ ꢀ46:0 (c 1.0,
ꢁ
CHCl3); lit.11
½
a 2D5
ꢁ
¼ ꢀ46:0 (c 1.0, CHCl3); 98% ee (Mosher ester);
IR (CHCl3, cmꢀ1) 3441.7, 2978.6, 2935.7, 1734.0, 1636.1, 1458.1;
1H NMR (200 MHz, CDCl3):
d 4.12–4.22 (m, 3H), 3.20 (d,
J = 3.8 Hz, 1H), 2.42–2.45 (m, 2H), 1.21–1.31 (m, 6H); 13C NMR
(50 MHz, CDCl3): d 172.5, 64.2, 60.5, 43.2, 22.6, 14.1. Anal. Calcd
for C6H12O3: C, 54.53; H, 9.15. Found: C, 54.56; H, 9.35.
ether to give 11 as
a
colorless liquid. Yield: 6.83 g (98%);
4.10. (R)-(ꢀ)-Ethyl (tert-butyldimethyl silyloxy)butyrate, 14
½
a 2D5
ꢁ
¼ ꢀ10:0 (c 1.0, CHCl3); IR (neat, cmꢀ1): 2929, 2856, 1471,
1462, 1455, 1373, 1361; 1H NMR (200 MHz, CDCl3): d 7.31–7.33
(m, 5H), 4.48 (s, 2H), 3.72–3.81 (m, 1H), 3.45 (t, J = 6.4 Hz, 2H),
1.33–1.63 (m, 6H), 1.12 (d, J = 6.1 Hz, 3H), 0.88 (s, 9H), 0.04 (s,
6H); 13C NMR (50 MHz, CDCl3): d 138.7, 128.2, 127.5, 127.3, 72.8,
70.3, 68.4, 39.5, 29.8, 25.9, 23.8, 22.4, 18.1, ꢀ4.4, ꢀ4.7. Anal. Calcd
for C19H34O2Si: C, 70.75; H, 10.62. Found: C, 70.78; H, 10.77.
To
a
solution of ethyl (R)-(ꢀ)-3-hydroxybutyrate 13 (7.0 g,
52.97 mmol) in dry CH2Cl2 (300 mL) at 0 °C were added imidazole
(7.21 g, 105.94 mmol) and tert-butyldimethylsilyl chloride (11.98 g,
79.46 mmol). The reaction mixture was then stirred at 25 °C for 2 h.
After completion of reaction (monitored by TLC), it was diluted with
CH2Cl2, washed with water, brine, and dried over anhydrous
Na2SO4. Concentration and purification by column chromatography
with petroleum ether/ethyl acetate (49:1 v/v) gave aldehyde 14 as a
4.7. (R)-5-(tert-Butyldimethylsilyloxy)hexan-1-ol, 12
colorless liquid. Yield: 12.66 g, (97%); ½a D25
¼ ꢀ26:0 (c 1.0, CH2Cl2);
ꢁ
A mixture of benzyl ether 11 (6 g, 18.60 mmol), 10% Pd/C, and
catalytic amount of triethylamine (2 drops) was stirred under H2
(1 atm) at 25 °C. After completion of reaction (monitored by TLC),
it was filtered through Celite (MeOH eluent) and the solvent evap-
orated under reduced pressure to afford the title compound as a
lit.12
½
a 2D5
ꢁ
¼ ꢀ25:5 (c 1.0, CH2Cl2); IR (CHCl3 cmꢀ1) 2958, 2931,
2897, 2857, 1739, 1473, 1447; 1H NMR (200 MHz, CDCl3): d 4.19–
4.28 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 2.44 (dd, J = 7.4, 14.5 Hz, 1H),
2.32 (dd, J = 5.4, 14.5 Hz, 1H), 1.22 (t, J = 7.2 Hz, 3H), 1.17 (d,
J = 6.1 Hz, 3H), 0.82 (s, 9H), d 0.05 (s, 3H), d 0.04 (s, 3H); 13C NMR
(50 MHz, CDCl3): d 171.2, 65.8, 59.9, 44.8, 25.7, 23.9, 17.9, 14.2,
ꢀ4.5, ꢀ5.0. Anal. Calcd for C12H26O3Si: C, 58.49; H, 10.63. Found:
C, 58.54; H, 10.56.
slightly yellow colored oil. Yield: 4.19 g (97%); ½a D25
¼ ꢀ13:8 (c
ꢁ
1.6, CHCl3); IR (neat, cmꢀ1): 3438.4, 2930.4, 2857.9, 1225.6,
1099.5, 1050.13; 1H NMR (200 MHz, CDCl3): d 3.70–3.78 (m, 1H),
3.59 (t, J = 6.3, 2H), 1.62 (br s, 1H), 1.32–1.55 (m, 6H), 1.09 (d,
J = 6.1 Hz, 3H), 0.84 (s, 9H), 0.04 (s, 6H); 13C NMR (50 MHz, CDCl3):
d 68.5, 62.6, 39.4, 32.7, 25.9, 23.7, 21.7, 18.1, ꢀ4.41, ꢀ4.71. Anal.
Calcd for C12H28O2Si: C, 62.01; H, 12.14. Found: C, 62.07; H, 12.14.
4.11. (R)-(ꢀ)-Ethyl (tert-butyldimethylsilyloxy)butanal, 15
To a stirred solution of ester 14 (11.50 g, 46.69 mmol) in dry tol-
uene (250 mL),
a solution of diisobutylaluminium hydride
4.8. (R)-5-(tert-Butyldimethylsilyloxy)hexanal, 3
(46.8 mL, 1 M in cyclohexane) was added dropwise at ꢀ78 °C and
stirred at this temperature for 1 h. After completion of reaction
(monitored by TLC), it was diluted with a saturated solution of Ro-
chelle salt and stirred for further 3 h. The organic phase was sepa-
rated and the aqueous phase was extracted twice with CH2Cl2. The
combined organic phase was then washed with water, brine, and
dried over anhydrous Na2SO4. Removal of solvent under reduced
pressure and column chromatographic purification with petroleum
ether/ethyl acetate (19:1 v/v) gave aldehyde 15 as a colorless li-
To a well-stirred solution of alcohol 12 (4.00 g, 17.21 mmol) in
DMSO (30 mL), 2-iodoxybenzoic acid (9.64 g, 34.42 mmol) was
added in one portion. The reaction mixture was then stirred for
1 h at 25 °C. After the completion of reaction (monitored by TLC),
it was diluted with water and diethyl ether. Subsequent filtration
(diethyl ether eluent) and washing the filtrate with water, brine
followed by drying over anhydrous Na2SO4 and removal of solvent
under reduced pressure gave crude product which on chromato-
graphic separation with petroleum ether/ethyl acetate (19:1 v/v)
gave the intermediate aldehyde 3 as a light yellow colored liquid.
quid. Yield: 8.03 g, 85%;
½
a 2D5
ꢁ
¼ ꢀ13:6 (c 1.6, CH2Cl2); lit.12
½
a 2D5
ꢁ
¼ ꢀ11:3 (c 1.0, CH2Cl2); IR (CHCl3, cmꢀ1) 2957, 2930, 2896,
2858, 1729, 1473, 1463, 1377, 1362; 1H NMR (200 MHz, CDCl3):
d 9.76 (dd, J = 2.1, 2.7 1H), 4.25–4.40 (m, 1H), 2.40–2.59 (m, 2H),
1.19 (d, J = 6.2 Hz, 3H), 0.84 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C
NMR (50 MHz, CDCl3): d 202.0, 64.5, 52.9, 25.7, 24.1, 17.9, ꢀ4.4,
ꢀ5.0. Anal. Calcd for C10H22O2Si: C, 59.35; H, 10.96. Found: C,
59.38; H, 10.97.
Yield: 3.89 g (98%); ½a D25
ꢁ
¼ ꢀ12:0 (c 3.0, CHCl3); IR (neat, cm–1):
3020, 2930, 2857, 1722, 1572, 1472, 1215; 1H NMR (200 MHz,
CDCl3): d 9.71 (t, J = 1.8 Hz, 1H), 3.71–3.83 (m, 1H), 2.33–2.39 (dt,
J = 7.1, 8.8 Hz, 2H), 1.54–1.70 (m, 2H), 1.35–1.43(m, 2H), 1.09 (d,
J = 6.0 Hz, 3H), 0.84 (s, 9H), 0.05 (s, 6H); 13C NMR (50 MHz, CDCl3):
d 202.0, 67.6, 43.4, 38.46, 25.40, 23.26, 17.85, 17.59, ꢀ4.84, ꢀ5.23.
Anal. Calcd for C12H26O2Si: C, 62.55; H, 11.37. Found: C, 62.65; H,
11.77.
4.12. (R)-(ꢀ)-Ethyl 5-tert-butyldimethylsiloxyhex-2-enoate, 6
To a solution of aldehyde 15 (7.00 g, 34.59 mmol) in dry THF
(200 mL) at 25 °C was added Ph3P@CHCOOEt (18.08 g,
51.89 mmol) and the reaction mixture was stirred for 12 h. After
completion of reaction (monitored by TLC), the solvent was dis-
tilled off under reduced pressure and the crude mass on column
chromatographic purification with petroleum ether/ethyl acetate
4.9. (R)-Ethyl (ꢀ)-3-hydroxybutyrate, 13
Ethyl acetoacetate 7 (7.50 g, 57.69 mmol) and dry methanol
(25 mL) were mixed and deoxygenated with flowing nitrogen for
5 min. The catalyst [(R)-Ru(BINAP)Cl2]2ꢂNEt3 (50 mg, 0.1 mol %)
was added along with 2 N HCl (0.05 mL, 0.1 mol %). The mixture
was transferred to a standard Parr reactor apparatus and flushed
(19:1 v/v) gave the a,b-unsaturated ester 6 as a slightly yellow col-
ored liquid. Yield: 8.76 g, (93%); ½a D25
ꢁ
¼ ꢀ15:8 (c 2.4, CHCl3, cmꢀ1);

V. Rawat et al. / Tetrahedron: Asymmetry 20 (2009) 2173–2177
2177
IR (CHCl3) 2930, 2857, 1724, 1655, 1463, 1376; 1H NMR (200 MHz,
4.15. Decarestrictine L, 1
CDCl3): d 6.83–6.94 (m, 1H), 5.82 (d, J = 15.5 Hz, 1H), 4.2 (q,
J = 7.1 Hz, 2H), 2.31 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 1.18 (d,
J = 6.1 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (50 MHz, CDCl3):
d 170.7, 146.7, 128.2, 67.9, 59.9, 42.4, 25.7, 23.7, 18.0, 14.2, ꢀ4.58,
ꢀ4.88. Anal. Calcd for C14H28O3Si: C, 61.72; H, 10.36. Found: C,
61.90; H, 11.86.
To a well-stirred solution of aminooxy olefinic ketone 2 (500 mg,
1.23 mmol) in ethanol was added copper acetate (750 mg,
30 mol %). The reaction mixture was then stirred overnight at
25 °C. After completion of reaction (monitored by TLC), the solvent
was removed under reduced pressure and the residue was dis-
solved in dry THF. To this, a solution of 1 M tetrabutylammonium
fluoride (2.55 mL, 2 equiv) was added at 25 °C. The reaction mixture
was stirred at this temperature for 6 h after which the solvent was
removed under reduced pressure and the residue was subjected to
column chromatography with petroleum ether/ethyl acetate (17:3
v/v) to afford decarestrictine L 1 as an oily liquid.
4.13. (R)-(ꢀ)-Ethyl (tert-butyldimethylsilyloxy)hexanal, 3
A mixture of a,b-unsaturated ester 6 (8 g, 29.36 mmol), 10% Pd/
C, and catalytic amount of triethylamine (2 drops) in MeOH
(40 mL) was stirred under H2 (1 atm) at 25 °C for 12 h. After com-
pletion of reaction (monitored by TLC), it was filtered over Celite
plug (MeOH eluent) and the solvent evaporated under reduced
pressure to give the corresponding saturated ester. To a stirred
solution of the saturated ester in dry toluene (150 mL), a solution
of diisobutylaluminium hydride (29.4 mL, 1 M in cyclohexane)
was added dropwise at ꢀ78 °C and was stirred at this temperature
for 1 h. After completion of reaction (monitored by TLC) the reac-
tion mixture was diluted with a saturated solution of Rochelle salt
and was stirred for further 3 h. The organic phase was separated
and the aqueous phase extracted twice with CH2Cl2. The combined
organic phase was then washed with water, brine, and dried over
anhydrous Na2SO4. Removal of solvent under reduced pressure
and column chromatographic purification with petroleum ether/
ethyl acetate (19:1 v/v) gave aldehyde 3 as a colorless liquid. Yield:
Yield: 127 mg (60%);
½
a 2D5
ꢁ
¼ þ28:6 (c 0.5, CHCl3) lit.4
½
a 2D5
ꢁ
¼ þ28:8 (c 0.49, CHCl3); IR (neat, cmꢀ1): 3415, 2965, 2853,
1712, 1598, 1440; 1H NMR (500 MHz, CDCl3):
d 4.03 (q,
J = 6.5 Hz, 1H), 3.97–3.94 (m, 1H), 3.43–3.39 (m, 1H), 2.73 (d,
J = 6.5 Hz, 2H), 2.21 (s, 2H), 2.04 (br s, 1H), 1.90–1.57 (m, 4H),
1.22 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 207.7, 72.0,
69.4, 67.4, 46.3, 30.5, 28.2, 27.0, 18.4. Anal. Calcd for C9H16O3: C,
62.77; H, 9.36. Found: C, 62.68; H, 9.38.
Acknowledgments
V.R. and P.V.C. thank CSIR, New Delhi for the award of research
fellowships. The authors are thankful to Dr. B. D. Kulkarni, Head,
Chemical Engineering and Process Development Division for his
encouragement and support.
5.55 g, (82%) (over two steps); ½a D25
¼ ꢀ12:0 (c 3.0, CHCl3); IR
ꢁ
(CHCl3, cmꢀ1) 3019, 2930, 2956, 2857, 1722, 1572, 1472, 1439;
1H NMR (200 MHz, CDCl3): d 9.76 (t, J = 1.8 Hz, 1H), 3.68–3.83
(m, 1H), 2.34–2.41 (dt, J = 7.1, 8.8 Hz, 2H), 1.58–1.70 (m, 2H),
1.35–1.43 (m, 2H), 1.10 (d, J = 6.1 Hz, 3H), 0.84 (s, 9H), 0.04 (s,
6H); 13C NMR (50 MHz, CDCl3): d 202.0, 67.6, 43.4, 38.5, 25.4,
23.3, 17.8, 17.6, ꢀ4.84. ꢀ5.23. Anal. Calcd for C12H26O2Si: C,
62.55; H, 11.37. Found: C, 62.65; H, 11.38.
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oily liquid. Yield: 2.06 g (60%); ½a D25
¼ ꢀ12:5 (c 4.0, CHCl3); IR (neat,
ꢁ
cmꢀ1): 3155, 2956, 2930, 2857, 1677, 1472, 1377; 1H NMR
(200 MHz, CDCl3): d 7.24–7.16 (m, 2H), 6.93–6.82 (m, 3H), 6.74–
6.63 (dd, J = 6.6, 16.2 Hz, 1H), 6.23 (d, J = 16.2 Hz, 1H), 4.38–4.28
(m, 1H), 3.86–3.73 (m, 1H), 2.23 (s, 3H), 1.96–1.44 (m, 4H), 1.09
(d, J = 6.1 Hz, 3H), 0.84 (s, 9H), 0.04 (s, 6H); 13C NMR (50 MHz,
CDCl3)): d 197.9, 148.4, 145.9, 131.7, 128.9, 122.1, 114.3, 83.2,
68.1, 34.8, 29.3, 27.3, 25.9, 23.8, 18.1, ꢀ4.27, ꢀ4.7. Anal. Calcd for
C21H35NO3Si: C, 66.80; H, 9.34; N, 3.71. Found: C, 66.85; H, 9.38;
N, 3.91.
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