Synthesis of (4R,6S,7R)-7-hydroxy-4,6-dimethyl-3-nonanone and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-2-octanone

Article abstract of DOI:10.1016/j.tetasy.2011.11.013

The synthesis of (4R,6S,7R)-7-hydroxy-4,6-dimethyl-3-nonanone and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-2-octanone is described as their acetates using a desymmetrization strategy as well as an Evans syn aldol strategy.

Full text of DOI:10.1016/j.tetasy.2011.11.013

Tetrahedron: Asymmetry 22 (2011) 2071–2079
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of (4R,6S,7R)-7-hydroxy-4,6-dimethyl-3-nonanone
and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-2-octanone
Gowravaram Sabitha a, , Chitti Srinivas a, Chittapragada Maruthi a, Jhillu Singh Yadav a,b
⇑
a Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500007, India
b Bee Research Chair, College of Food and Agriculture Science, King Saud University, Riyadh, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of (4R,6S,7R)-7-hydroxy-4,6-dimethyl-3-nonanone and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-
2-octanone is described as their acetates using a desymmetrization strategy as well as an Evans syn aldol
strategy.
Received 19 October 2011
Accepted 22 November 2011
Available online 21 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
O
The potential economic and environmental importance of bio-
logical pest control is an undergoing experimental evaluation,
and the successful use of natural insect attractants has been re-
ported by several groups. Insect attractants have been used to re-
duce pest populations by employing attractant-baited traps. The
relatively small amounts of synthetic attractants required, mini-
mizes the possibility of environmental pollution, and the species
specificity of many natural attractants reduces the risk of destroy-
ing beneficial insects such as predators, parasites, and pollinators
resistant to natural attractants is very unlikely. Thus the presence
of a synthetic approach has been very important in pheromone
research.
(CH2)7
Me(CH2)17
O
(4S)-methyl-3-heptanone
(3S,11S)-dimethylnonacosan-2-one
(CH2)4
(CH2)7OH
OH
O
(Z)-(14R)-methyl-8-hexadecen-1-ol
Figure 1. Examples of pheromones.
serricornin
(3S,11S)-Dimethylnonacosan-2-one (produced by females of
the German cockroach, Blattella germanica),1 (4S)-methyl-3-
heptanone (the principal alarm pheromone of the leaf-cutting
ant, Atta texana),2 (Z)-(14R)-methyl-8-hexadecen-1-ol (the der-
mestid beetle pheromone artifact),3 serricornin (an insect derived
sex pheromone), are a few examples of pheromones that attracted
the interest of synthetic chemists (Fig. 1).
Serricornin and its isomers are insect derived sex pheromones,
more effective as traps for the beetles Stegobium panecium and
Lasioderma serricorne. Francke and his co-workers have identified
stereoisomers of nor-serricornin (a stereoisomer of serricornin)
as the pheromone components of the bostrychid beetle, Dinoderus
bifoveolatus.
The only total synthesis of these stereoisomers was reported by
Mori et al.4 Starting from meso-2,4-dimethylglutaric anhydride.
Therefore, the synthesis of these isomers attracted our attention.
In a continuation of our interest in the exploitation of desymmet-
rization strategies for the synthesis of various natural products,5
we herein report the synthesis of (4R,6S,7R)-7-hydroxy-4,6-
dimethyl-3-nonanone 1 and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-
2-octanone 2 and their respective isomers 10, 20 as their acetates
3, 4, 30, 40, respectively. The compounds were also synthesized in
another route exploiting an Evans-aldol reaction.
The structures were established as (4R,6S,7R)-1 and (3R,5S,6R)-
2 as well as their stereoisomers (4R,6S,7S)-10 and (3R,5S,6S)-20 by
means of gas chromatography of their acetates 3, 4, 30, and 40
(Fig. 2).
2. Results and discussion
The intermediate 5 with three stereogenic centers was envis-
aged as a common intermediate for the synthesis of 3, 4, 30, 40 as
represented in the retrosynthetic analysis shown below (Scheme 1)
and could be made by two different strategies. In route a, the
desymmetrization of bicyclic olefin 8 was used, whereas in route
⇑
Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.013

2072
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2071–2079
methyl protons attached to sulfur in the xanthate group. Then it
was deoxygenated by tri-n-butyltin hydride in the presence of a
catalytic amount of AIBN as a radical initiator (Barton–McCombie
deoxygenation)8 to afford compound 6 in an 88% yield, which
was confirmed by 1H NMR analysis. 1H NMR of the 6 showed the
absence of proton resonance at d = 5.90 ppm corresponding to
the methane attached to the xanthate group.
OR
OR
O
O
(3R,5S,6R)-2 R=H
(3R,5S,6R)-4 R=Ac
(4R,6S,7R)-1 R=H
(4R,6S,7R)-3 R=Ac
The acetonide group within 6 was hydrolyzed using a catalytic
amount of PPTS in MeOH to yield diol 17. The primary hydroxyl
group in compound 17 was selectively tosylated with TsCl, Et3N,
and a catalytic amount of nBu2SnO in CH2Cl2 to furnish monotosyl-
ate 18 in a 95% yield,9 followed by reductive cleavage of the sulfo-
nate with LAH, in THF to form 19 in an 88% yield. Next, the
secondary hydroxyl group was protected as benzyl ether 20 using
NaH and BnBr in THF. Then the primary MOM group was deprotec-
ted by using a catalytic amount of pTSA in MeOH to yield the pri-
mary alcohol 5 in an 87% yield.
OR
O
OR
O
(3R,5S,6S)-2' R=H
(3R,5S,6S)-4' R=Ac
(4R,6S,7S)-1' R=H
(4R,6S,7S)-3' R=Ac
Figure 2. Structures of the pheromone components of a Bostrchid beetle (1 and 2),
and their stereoisomers (10 and 20).
Intermediate 5 was also prepared by another route employing an
Evans syn aldol reaction (Scheme 3). Accordingly propanal was sub-
jected to ‘Evans syn aldol’ reaction conditions10 employing an eno-
late of thiazolidinethione 10, affording aldol adduct 21 in an 85%
yield after column chromatography. Reductive cleavage of the chiral
axiliary using NaBH4, afforded diol 22. The diol 22 was treated with
benzaldehyde dimethyl acetal to yield benzylidine acetal 23 in a 91%
yield. Regioselective reductive acetal cleavage at the less hindered
oxygen with DIBAL-H11 at ꢀ15 °C afforded the primary alcohol 24
in a 90% yield. Oxidation of primary alcohol 24 using IBX in DMSO/
CH2Cl2 gave aldehyde 25. Aldehyde 25 was again subjected to an
Evans syn aldol reaction with thiazolidinethione 10. Thus, two aldol
reactions allowed the incorporation of four stereocenters. Reductive
cleavage of the chiral axiliary 9 using NaBH4, afforded diol 26. Silyla-
tion of the primary alcohol provided TBDMS ether 27 in a 95% yield.
The free hydroxyl group was converted into the xanthate ester 28
using NaH, carbon disulfide, and methyl iodide, and deoxygenated
by using tri-n-butyltin hydride in the presence of a catalytic amount
of AIBN as a radical initiator (Barton–McCombie deoxygenation)8 to
afford compound 29 in an 87% yield. Removal of the silyl group pro-
vided compound 5, which was identical in all respects with the alco-
hol 5 prepared in Scheme 2.
b, an Evans syn aldol reaction was utilized. Subsequent Grignard
and oxidation reactions as well as Mitsunobu inversion provided
the respective target molecules.
The synthesis of (4R,6S,7R)-7-hydroxy-4,6-dimethyl-3-nona-
none
1 and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-2-octanone 2
started from the known bicyclic lactone 7,5e which was prepared
using a desymmetrization strategy. The key fragment 5, which
contains all the required stereocenters of target molecules
3, 30, 4, 40, was prepared on the basis of the desymmetrization of
bicyclic olefin 8 using Brown’s chiral hydroboration with dii-
sopropylcamphenylborane [(+) Ipc2BH].
A high enantiomeric
purity (97% ee) was achieved in the hydroboration of 8 using (+)-
Ipc2BH prepared from borane-dimethyl sulfide complex and an
excess of (ꢀ)-a-pinene (Scheme 2). The chiral bicyclic alcohol 11
was converted into the bicyclic lactone 7 by following a standard
procedure.5e Next, attention was directed to the opening of lactone
7. Thus, the opening of bicyclic lactone 7 with LAH yielded triol 12
in a 90% yield. The chemoselective protection of the 1,3-diol using
2,2-DMP, pTSA (catalytic) in CH2Cl2 afforded the corresponding
acetonide 13 in an 89% yield, which was confirmed by 13C NMR
spectrum analysis (d = 98.0 ppm for the acetonide carbon flanked
by two oxygen atoms). After protection of the primary hydroxyl
group as MOM ether6 14 using MOMCl and DIPEA, debenzylation
of 14 under Birch conditions7 with Li/liq NH3 in THF gave alcohol
15 in a 91% yield. The C-3 oxygen of compound 15 needs to be
deoxygenated to gain the complete stereochemistry of the target
molecules. Accordingly, compound 15 was converted into xanthate
ester 16 using NaH, carbon disulfide and methyl iodide. The 1H
NMR spectrum of xanthate ester 16 showed a characteristic signal
as a dd (doublet of doublets) at d = 5.90 ppm for the methine
proton attached to xanthate group, a singlet at d = 2.56 ppm for
The intermediate 5 prepared by these two routes was utilized
for the preparation of target molecules. Oxidation of compound 5
using IBX in DMSO/DCM gave aldehyde 30 (Scheme 4). Grignard
reaction of aldehyde 30 with EtMgBr in dry THF gave a secondary
alcohol, which without isolation was converted into a keto com-
pound 31.
Removal of the benzyl group afforded hydroxyl product 10. The
1H NMR spectrum of debenzylated product 10 was found to be com-
plicated due to a mixture of open and hemi-acetal tautomers and
thus was used directly for acetylation. Therefore 10 was immediately
Route a
O
O
O
3, 3', 4, 4'
OBn
OH
O
O
OMOM
OBn
7
5
6
Route b
Ph
Ph
O
N
N
S
S
OBn
8
O
OH
OBn
O
S
S
9
10
Scheme 1. Retrosynthetic analysis.

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2071–2079
2073
O
O
O
O
HO
ref [5e]
ref [5e]
a
O
OH
OH
OBn
OH
OBn
OBn
OBn
11
8
7
12
b
c
d
OH
OR
OBn
OBn
13
OR
HO
O
O
O
O
O
O
R = MOM
14
15
g
e
f
OR1
OH
OMOM
OMOM
OR
O
O
OH
O
O
17
6
R1 = CS2Me
16
j
h
i
OMOM
18
OMOM
OMOM
OH
OBn
OH
OTs
19
20
k
OBn
OH
5
Scheme 2. Reagents and conditions: (a) LAH, dry THF, reflux, 4 h, 90%; (b) 2,2 DMP, pTSA, dry CH2Cl2, 0 °C to rt, 3 h, 89%; (c) MOMCl, i-Pr2NEt, dry CH2Cl2, 0 °C to rt, 4 h, 90%;
(d) Li, liq NH3, THF, 10 min, 91%; (e) NaH, CS2, MeI, dry THF, 0 °C to rt, 5 h, 92%; (f) nBu3SnH, AIBN, toluene, reflux, 2 h, 88%; (g) PPTS, MeOH, 0 °C to rt, 3 h, 85%; (h) p-TsCl,
nBu2SnO, Et3N, dry CH2Cl2, 0 °C to rt, 4 h, 95%; (i) LAH, dry THF, reflux 3 h, 88%; (j) NaH, BnBr, dry THF, 0 °C to rt 5 h, 90%; (k) PTSA, MeOH, 0 °C to rt, 6 h, 87%.
converted into its acetate by treating with acetic anhydride, trieth-
ylamine, and a catalytic amount of DMAP to afford the final product
30. Mitsunobu inversion12 of hydroxy compound 10 at C-7 using TPP,
DEAD in the presence of AcOH directly gave final product 3.
Similarly, Grignard reaction of aldehyde 30 with MeMgBr in dry
Ether gave a secondary alcohol, which without isolation was con-
verted into a keto compound 32. Removal of the benzyl group
afforded hydroxy product 20, which by following the above proce-
dure was converted into final products 40 and 4.
UV light). Light petroleum ether (bp 60–80 °C) was used. Yields re-
fer to chromatographically and spectroscopically (1H, 13C NMR)
homogeneous materials. Air-sensitive reagents were transferred
by syringe or double-ended needle. Evaporation of solvents was
performed at reduced pressure on a Buchi rotary evaporator. 1H
and 13C NMR spectra of samples in CDCl3 were recorded on Varian
FT-200 MHz (Gemini) and Bruker UXNMR FT-300 MHz (Avance)
spectrometers. Chemical shifts (d) are reported relative to TMS
(d = 0.0) as an internal standard. Mass spectra were recorded in
E1 conditions at 70 eV on an LC–MSD (Agilent technologies) spec-
trometers. All high resolution spectra were recorded on QSTAR XL
hybrid ms/ms system (Applied Bio systems/MDS sciex, foster city,
USA), equipped with an ESI source (IICT, Hyderabad). Column chro-
matography was performed on silica gel (60–120 mesh) supplied
by Acme Chemical Co., India. TLC was performed on Merck 60 F-
254 silica gel plates. Optical rotations were measured with JASCO
DIP-370 Polarimeter at 25 °C.
3. Conclusion
In summary, the versatility of a desymmetrization strategy and
chlorotitanium mediated asymmetric aldol reactions was demon-
strated in a higly stereoselective fashion for the synthesis of vari-
ous stereoisomers of serricornin.
4. Experimental
4.1. General
4.1.1. (3S,4R,5S,6S)-5-(Benzyloxy)-4,6-dimethylheptane-1,3,7-
triol 12
To a stirred suspension of LiAlH4 (0.541 g, 14.23 mmol) in dry
THF (30 mL) at 0 °C, a solution of lactone 7 (2.62 g, 9.49 mmol) in
dry THF (20 mL) was added dropwise. The reaction mixture was re-
fluxed for 4 h and cooled to 0 °C, diluted with ether and quenched
Reactions were conducted under N2 in anhydrous solvents such
as CH2Cl2, THF, Benzene, Toluene, DMSO, and MeOH. All reactions
were monitored by TLC (silica-coated plates and visualizing under

2074
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2071–2079
Ph
Ph
b
88%
O
O
a
c
N
N
S
S
OH
OH
O
O
OH
S
S
22
23
10
21
Ph
N
f
e
d
S
O
OBn
OH
OH
OBn
OH
O
OH
OBn
S
24
25
9
b
g
h
90%
TBSO
OR
28
OBn
R = CS2Me
OBn
TBSO
OH
27
OBn
26
j
i
OTBS
OBn
OH
OBn
29
5
Scheme 3. Reagents and conditions: (a) TiCl4, i-Pr2NEt, propanal, dry CH2Cl2, 1 h, 85%; (b) NaBH4, MeOH, 0 °C to rt, 1 h, 88%; (c) Ph–CH(OMe)2, PPTS, dry CH2Cl2, 0 °C to rt, 2 h,
91%; (d) DIBAL-H, dry CH2Cl2, ꢀ15 °C 1 h, 90%. (e) IBX, DMSO, dry CH2Cl2, 0 °C to rt, 2 h, 88% (f) TiCl4, i-Pr2NEt, 10, dry CH2Cl2, 1 h, 80%; (g) TBDPS-Cl, imidazole, CH2Cl2, 0 °C to
rt, 2 h, 95%; (h) NaH, CS2, MeI, 0 °C to rt, dry THF 0 °C to rt, 5 h, 91%; (i) nBu3SnH, AIBN, Toluene, reflux, 2 h, 87%; (j) PTSA, MeOH, 0 °C to rt, 30 min, 93%.
with dropwise addition of saturated aqueous Na2SO4. The solid
material was filtered and washed thoroughly with hot ethyl ace-
tate several times. The combined organic layers were dried over
anhydrous Na2SO4, the solvent was removed under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (EtOAc/pet-ether, 8:2) to afford the pure compound 12
5H), 4.63 (ABq, J = 11.3, 3.0 Hz, 2H), 4.25 (dt, J = 12.1, 2.7 Hz, 1H),
3.92 (dt, J = 12.1 2.7 Hz, 1H), 3.80 (dd, J = 11.3, 3.8 Hz, 2H), 3.53
(dd, J = 11.3, 4.5 Hz, 1H), 3.44 (dd, J = 9.1, 3.0 Hz, 1H), 2.64 (br s,
OH, 1H), 1.96–1.69 (m, 3H), 1.39 (s, 3H), 1.34 (s, 3H), 1.27–1.15
(m, 1H), 1.17 (d, J = 7.6 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d 138.2, 128.5, 127.7, 127.2, 98.0, 85.6, 75.2,
67.4, 64.4, 60.0, 41.4, 36.3, 30.0, 28.6, 19.6, 16.3, 10.4; ESI: m/
z = 345 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C19H30O4Na:
345.2041, found: 345.2035.
(2.41 g, 90%) as a viscous liquid. ½a D25
ꢁ
¼ ꢀ6:9 (c 1, CHCl3); IR (neat):
mmax 3397, 2931, 1637, 1457, 1053 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 7.38–7.27 (m, 5H), 4.67 (s, 2H), 4.22 (d, J = 10.6 Hz,
1H), 3.82–3.72 (m, 3H), 3.64 (dt, J = 14.3, 3.8 Hz, 1H), 3.49 (dd,
J = 7.6, 3.8 Hz, 1H), 3.37–3.31 (br s, OH, 1H), 2.56–2.46 (br s, OH,
1H), 2.10–1.98 (m, 1H), 1.94–1.79 (m, 2H), 1.75–1.66 (m, 1H),
1.45–1.34 (m, 1H), 1.11 (d, J = 7.5 Hz, 3H), 1.01 (d, J = 7.5 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d 138.0, 129.0, 128.5, 128.3, 88.6, 77.8,
70.9, 64.4, 62.2, 39.6, 38.2, 37.0, 15.4, 12.2; ESI: m/z = 305
[M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C16H26O4Na:
305.1728, found: 305.1738.
4.1.3. (S)-4-((2R,3S,4S)-3-(Benzyloxy)-5-(methoxymethoxy)-4-
methylpentan-2-yl)-2,2-dimethyl-1,3-dioxane 14
To a stirred solution of alcohol 13 (2.3 g, 7.13 mmol) in dry
i
CH2Cl2 (30 mL) at 0 °C under N2, Pr2NEt (2.43 mL, 14.26 mmol)
was added followed by dropwise addition of MOMCl (0.85 mL,
10.70 mmol). After the reaction was complete, the reaction mix-
ture was quenched by adding a saturated solution of NaHCO3
and the product was extracted with CH2Cl2. The combined organic
layers were dried over anhydrous Na2SO4. The residue was concen-
trated under reduced pressure and purified by silica gel column
chromatography (EtOAc/pet-ether, 1:19) to afford the pure com-
4.1.2. (2S,3S,4R)-3-(Benzyloxy)-4-((S)-2,2-dimethyl-1,3-dioxan-
4-yl)-2-methylpentan-1-ol 13
To a solution of triol 12 (2.35 g, 8.32 mmol) in dry CH2Cl2
(30 mL), 2,2-dimeothoxypropane (2.04 mL, 16.64 mmol) and pTSA
(0.16 g, 0.83 mmol) were added. The mixture was stirred at ambi-
ent temperature for 3 h. After completion of the reaction solid
NaHCO3 was added to neutralize the pTSA and filtered. The solvent
was removed under reduced pressure and the residue was purified
by silica gel column chromatography (EtOAc/pet-ether, 2:8) to af-
ford the pure monoacetonide 13 (2.38 g, 89%) as a white solid.
pound 14 (2.35 g, 90%) as a clear colorless liquid. ½a D25
¼ ꢀ2:0 (c
ꢁ
0.5, CHCl3); IR (neat): mmax 3445, 2931, 2880, 1633, 1451, 1377,
1100, 1046 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.33–7.20 (m,
;
5H), 4.60 (ABq, J = 11.3, 3.8 Hz, 2H), 4.55 (s, 2H), 4.22 (dt, J = 11.3,
2.3 Hz, 1H), 3.90 (dt, J = 12.1, 2.3 Hz, 1H), 3.79 (ddd, J = 11.3, 5.3,
1.5 Hz, 2H), 3.67 (dd, J = 9.8, 4.5 Hz, 1H), 3.35 (dd, J = 12.8, 3.0 Hz,
1H), 3.32 (s, 3H), 2.13–2.01 (m, 1H), 1.91–1.78 (m, 1H), 1.74–
1.64 (m, 1H), 1.37 (s, 3H), 1.33 (s, 3H), 1.25–1.13 (m, 1H), 1.10
(d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3,
½
a 2D5
ꢁ
¼ þ22:5 (c 1.5, CHCl3); IR (neat): mmax 3419, 2925, 1640,
1456, 1042 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.36–7.22 (m,
;

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2071–2079
2075
d, e
OH
OBn
5
b
80%
O
O
OAc
OAc
3'
3
a
O
OBn
d, f
31
60%
O
OBn
30
d, e
81%
O
O
OAc
OAc
4'
c
O
OBn
32
d, f
59%
4
Scheme 4. Reagents and conditions: (a) IBX, DMSO, CH2Cl2, 0 °C to rt, 2 h, 89%; (b) (i) Mg, EtBr, dry THF, 0 °C to rt, 2 h, 90%; (ii) IBX, DMSO, CH2Cl2, 0 °C to rt, 2 h, 92%; (c) (i)
Mg, MeI, dry Ether, 0 °C to rt, 2 h, 88%; (ii) IBX, DMSO, CH2Cl2, 0 °C to rt, 2 h, 90%; (d) 10% Pd/C, Benzene, rt, 4 h, (e) Et3N, Ac2O, DMAP, CH2Cl2, 0 °C to rt, 2 h; (f) TPP, AcOH,
DEAD, dry THF, 0 °C to rt, 1 h.
75 MHz): d 139.2, 128.3, 127.3, 126.8, 98.0, 96.4, 83.2, 74.7, 69.1,
67.5, 60.0, 55.0, 41.2, 36.1, 30.2, 28.8, 19.7, 16.7, 10.8; ESI: m/
z = 389 [M+Na]+.
using a syringe under N2. After stirring the reaction mixture at rt for
half an hour, the reaction mixture was cooled to 0 °C and CS2 (1.3 mL,
21.71 mmol) was added. After stirring for half an hour at 0 °C, MeI
(2.70 mL, 43.42 mmol) was added at the same temperature. After
completion of the reaction, the reaction mixture was cooled to 0 °C
and quenched by addition of satd solution of NH4Cl, and then the
product was extracted with EtOAc. The combined organic layers
were washed with brine, and dried over anhydrous Na2SO4. The sol-
vent was removed under reduced pressure and the residue was puri-
fied by silica gel column chromatography (EtOAc/pet-ether, 1:19) to
afford the pure compound 16 (1.83 g, 92%) as a clear yellow liquid.
4.1.4. (2S,3S,4S)-4-((S)-2,2-Dimethyl-1,3-dioxan-4-yl)-1-
(methoxymethoxy)-2-methylpentan-3-ol 15
To a freshly distilled ammonia (30 mL) in 100 mL two neck
roundbottomed flask fitted with a cold finger condenser, was
added lithium metal (0.44 g, 62.75 mmol) in fractions at –33 °C
and the resulting gray colored suspension was stirred for 30 min.
To this was added compound 14 (2.3 g, 6.27 mmol) in dry THF
(20 mL). The reaction mixture was then stirred for another
10 min at ꢀ33 °C and quenched by the addition of solid NH4Cl
and then the excess ammonia was allowed to evaporate. The resi-
due left was partitioned between water and ether and the aqueous
phase extracted with ether. The organic layers were combined,
washed once with water, brine, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography (EtOAc/pet-ether, 2:8)
to afford the pure compound 15 (1.57 g, 91%) as a clear colorless
½
a 2D5
ꢁ
¼ ꢀ9:0 (c 0.5, CHCl3); IR (neat): mmax 3450, 2929, 2859, 1736,
1613, 1512, 1459, 1375, 1233, 1045 cmꢀ1 1H NMR (CDCl3,
;
500 MHz): d 5.90 (dd, J = 8.8, 2.9 Hz, 1H), 4.56 (ABq, J = 9.5, 6.6 Hz,
2H), 3.91 (td, J = 11.7, 2.2 Hz, 1H), 3.84 (dt, J = 11.7, 2.2 Hz, 1H),
3.79 (ddd, J = 11.7, 5.1, 1.5 Hz, 1H), 3.67 (dd, J = 9.5, 4.4 Hz, 1H),
3.33 (s, 3H), 3.29 (dd, J = 9.5, 8.1 Hz, 1H), 2.56 (s, 3H), 2.32–2.22
(m, 1H), 2.01–1.92 (m, 1H), 1.90–1.78 (m, 1H), 1.30 (s, 3H), 1.28 (s,
3H), 1.18–1.12 (m, 1H), 1.05 (d, J = 7.3 Hz, 3H); 1.00 (d, J = 7.3 Hz,
3H); ESI: m/z = 389 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for
liquid. ½a 2D5
ꢁ
¼ ꢀ20:0 (c 0.5, CHCl3); IR (neat): mmax 3496, 2926,
C16H30O5NaS2: 389.1432, found: 389.1447.
2857, 1732, 1461, 1378, 1244, 1153, 1043 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 4.56 (s, 2H), 4.23 (dt, J = 12.1, 3.0 Hz, 1H), 3.95 (dt,
J = 11.3, 2.7 Hz, 1H), 3.84 (ddd, J = 12.1, 5.3, 1.5 Hz, 1H), 3.66 (dd,
J = 9.8, 4.5 Hz, 1H), 3.51 (dd, J = 9.8, 6.8 Hz, 1H), 3.40 (q, J = 12.1,
6.1, 1.5 Hz, 1H), 3.34 (s, 3H), 3.26 (d, J = 6.8 Hz, 1H), 2.00–1.73
(m, 3H), 1.45 (s, 3H), 1.35 (s, 3H), 1.29–1.17 (m, 1H), 1.03 (d,
J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 98.5, 96.6, 76.8, 70.8, 69.7, 60.1, 55.2, 38.4, 36.5, 29.8, 26.8,
19.1, 15.3, 11.9; ESI: m/z = 299 [M+Na]+. HRMS (ESI): [M+Na]+ m/
z calcd for C14H28O5Na: 299.1834, found: 299.1843.
4.1.6. (S)-4-((2S,4R)-5-(Methoxymethoxy)-4-methylpentan-2-
yl)-2,2-dimethyl-1,3-dioxane 6
To a solution of xanthate 16 (1.75 g, 4.77 mmol) in toluene
(30 mL), in a two neck 100 mL round bottomed flask equipped with
stirring bar and a reflux condenser with a N2 inlet, was added
(nBu)3SnH (2.05 mL, 7.64 mmol) followed by a catalytic amount
of AIBN (radical initiator). The reaction mixture was refluxed for
2 h. After the reaction was complete, the solvent was evaporated
under reduced pressure and the residue was directly purified by
silica gel column chromatography (EtOAc/pet-ether, 1:19) to fur-
nish pure compound 6 (1.09 g, 88%) as a clear colorless liquid.
4.1.5. O-(2S,3S,4R)-4-((S)-2,2-Dimethyl-1,3-dioxan-4-yl)-
1-(methoxymethoxy)-2-methylpentan-3-yl S-methyl
carbonodithioate 16
½
a 2D5
ꢁ
¼ þ5:5 (c 1, CHCl3); IR (neat): mmax 2928, 2877, 1458, 1378,
1105, 1048 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 4.56 (s, 2H), 3.89
;
Toa suspensionofNaH(0.26 g, 10.85 mmol)indryTHF(20 mL)at
0 °C was added the alcohol 15 (1.5 g, 5.42 mmol) in dry THF (20 mL)
(td, J = 11.7, 2.3 Hz, 1H), 3.80 (ddd, J = 11.7, 5.4, 1.6 Hz, 1H), 3.60
(ddd, J = 11.7, 4.7, 3.3 Hz, 1H), 3.37 (dd, J = 9.3, 5.4 Hz, 1H), 3.32

2076
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2071–2079
(s, 3H), 3.23 (dd, J = 9.4, 7.0 Hz, 1H), 1.86–1.75 (m, 1H), 1.72–1.44
(m, 5H), 1.39 (s, 6H), 0.95 (d, J = 6.2 Hz, 3H), 0.90 (d, J = 7.0 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d 98.1, 96.5, 72.6, 72.3, 60.1,
55.0, 36.3, 35.3, 30.9, 29.8, 28.2, 19.2, 18.5, 15.3; ESI: m/z = 299
[M+K]+.
mide (0.25 mL, 2.05 mmol) was added and the mixture was again
refluxed for 4 h. The reaction mixture was quenched by using ice
and extracted with ether. The organic layer was dried over anhy-
drous Na2SO4 and the solvent was removed under reduced pres-
sure, and the residue was purified by silica gel column
chromatography (EtOAc/pet-ether, 1:19) to afford the pure com-
4.1.7. (3S,4S,6R)-7-(Methoxymethoxy)-4,6-dimethylheptane-
1,3-diol 17
pound 20 (0.518 g, 90%) as a light yellow liquid. ½a D25
¼ ꢀ13:0 (c
ꢁ
0.5, CHCl3); IR (neat): mmax 2959, 2928, 2877, 1459, 1147, 1105,
To a stirred solution of compound 6 (1.03 g 3.95 mmol) in
MeOH (20 mL) was added a catalytic amount of pPTS. The reaction
mixture was stirred at room temperature for 3 h. After completion
of the reaction, NaHCO3 was added to neutralize the pPTS and
filtered. The filtrate was concentrated under reduced pressure
and purified by silica gel column chromatography (EtOAc/pet-
ether, 7:3) to afford the pure compound 17 (0.74 g, 85%) as a
1047 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.33–7.21 (m, 5H), 4.54
;
(s, 2H), 4.49 (ABq, J = 11.3, 3.8 Hz, 2H), 3.34 (dd, J = 9.1, 5.3 Hz,
1H), 3.30 (s, 3H), 3.22 (dd, J = 9.1, 6.8 Hz, 1H), 3.16–3.08 (m, 1H),
1.89–1.71 (m, 2H), 1.63–1.44 (m, 4H), 0.94 (d, J = 6.8 Hz, 3H),
0.92 (t, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 139.3, 128.2, 127.5, 127.2, 96.3, 84.0, 72.8, 71.8, 55.0,
37.1, 32.7, 31.1, 23.4, 18.6, 15.5, 10.7; ESI: m/z = 317 [M+Na]+.
HRMS (ESI): [M+Na]+ m/z calcd for C18H30O3Na: 317.2092, found:
317.2084.
viscous liquid. ½a D25
ꢁ
¼ ꢀ4:2 (c 1.5, CHCl3); IR (neat): mmax 3411,
2928, 1461, 1384, 1109, 1044 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d
4.58 (s, 2H), 3.89–3.74 (m, 3H), 3.33 (s, 3H), 3.36–3.30 (m, 2H),
2.59 (br s, OH, 2H), 1.89–1.68 (m, 2H), 1.67–1.48 (m, 4H), 0.94
(d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 96.5, 74.3, 73.1, 62.1, 55.1, 37.1, 36.1, 35.4, 30.7, 18.2,
14.6; ESI: m/z = 243 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for
C11H24O4Na: 243.1572, found: 243.1579.
4.1.11. (2R,4S,5S)-5-(Benzyloxy)-2,4-dimethylheptan-1-ol 5
To a stirred solution of compound 20 (0.45 g 1.52 mmol) in
MeOH (10 mL) was added a catalytic amount of pTSA. The reaction
mixture was stirred at room temperature for 6 h. After completion
of the reaction solid NaHCO3 was added to neutralize the pTSA and
filtered. The filtrate was concentrated under reduced pressure and
purified by silica gel column chromatography (EtOAc/pet-ether,
3:7) to afford pure compound 5 (0.33 g, 87%) as a colorless liquid.
Compound 5 (0.332 g, 93%) was prepared from compound 29
(0.52 g 1.426 mmol) following the procedure described above.
4.1.8. (3S,4S,6R)-3-Hydroxy-7-(methoxymethoxy)-4,6-
dimethylheptyl 4-methylbenzenesulfonate 18
A solution of 17 (0.67 g, 3.04 mmol) in dry CH2Cl2 (20 mL), con-
taining Et3N (0.55 ml, 3.95 mmol), was cooled to 0 °C and treated
with p-TsCl (0.58 g, 3.04 mmol) and a catalytic amount of nBu2SnO.
The reaction mixture was stirred at room temperature for 4 h, after
which it was diluted with water and extracted with CH2Cl2. The or-
ganic layer was washed with brine and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography
(EtOAc/pet-ether, 1:9) to afford the pure compound 18 (1.08 g,
½
a 2D5
ꢁ
¼ ꢀ1:8 (c 1, CHCl3); IR (neat): mmax 3413, 2959, 2925, 2868,
1457, 1057 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.34–7.20 (m,
;
5H), 4.50 (ABq, J = 11.7 Hz, 2H), 3.42 (dd, J = 10.3, 4.4 Hz, 1H),
3.34 (dd, J = 10.3, 6.5 Hz, 1H), 3.18–3.10 (m, 1H), 1.88–1.76 (m,
1H), 1.66–1.44 (m, 5H), 0.92 (t, J = 7.3 Hz, 3H), 0.91 (d, J = 7.3 Hz,
3H), 0.90 (d, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 139.2,
128.2, 127.7, 127.3, 84.0, 71.8, 67.9, 36.2, 33.2, 32.6, 23.2, 17.7,
15.6, 10.6; ESI: m/z = 273 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd
for C16H26O2Na: 273.1830, found: 273.1818.
95%) as a light yellow liquid. ½a D25
¼ ꢀ21:0 (c 0.5, CHCl3); IR (neat):
ꢁ
mmax 3465, 2925, 2855, 1738, 1462, 1368, 1244, 1109, 1044 cmꢀ1
;
1H NMR (CDCl3, 400 MHz): d 7.78 (d, J = 8.0 Hz, 2H) 7.33 (d,
J = 8.8 Hz, 2H) 4.56 (s, 2H), 4.27–4.20 (m, 1H), 4.14–4.08 (m, 1H),
3.68–3.62 (m, 1H), 3.33 (s, 3H), 3.31 (d, J = 5. 8 Hz, 2H), 2.47 (s,
3H), 1.94–1.66 (m, 3H), 1.60–1.47 (m, 2H), 1.02–0.94 (m, 1H),
0.93 (d, J = 7.3 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 171.3, 144.7, 129.8, 127.8, 96.5, 73.0, 70.6, 62.3, 55.1,
37.2, 35.6, 33.4, 30.7, 20.9, 18.1, 14.1; ESI: m/z = 397 [M+Na]+.
HRMS (ESI): [M+Na]+ m/z calcd for C18H30O6NaS: 397.1660, found:
397.1668.
4.1.12. (2R,3S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-3-hyd-
roxy-2-methylpentan-1-one 21
To a solution of (3.0 g, 11.30 mmol) thiazolidinethione propio-
nate 10 in dry CH2Cl2 (50 mL) was added (TiCl4 1 M in CH2Cl2) at
0 °C (11.52 mL, 11.52 mmol) forming a red-orange slurry. After
5 min, DIPEA (2.16 mL, 12.66 mmol) was slowly added forming
the characteristic enolate color (deep red). After 30 min at
ꢀ78 °C, propionaldehyde (1.64 mL, 22.60 mmol) freshly distilled
under N2) in dry CH2Cl2 (20 mL) was added. Within 5 min, the color
had faded to a pale brown color, indicating consumption of the
enolate. The reaction mixture was quenched with saturated aque-
ous NH4Cl solution. It was diluted with CH2Cl2, and the product
was extracted with CH2Cl2 washed with brine. The combined or-
ganic layers were dried over anhydrous Na2SO4 and the solvent
was removed under reduced pressure and the residue was purified
by silica gel column chromatography (EtOAc/pet-ether, 1:19) to af-
ford the pure compound 21 (3.1 g, 85%) as a yellow viscous liquid.
4.1.9. (3S,4S,6R)-7-(Methoxymethoxy)-4,6-dimethylheptan-3-ol
19
Compound 18 (1.0 g, 2.67 mmol) was converted in 3 h into
compound 19 (0.48 g, 88%) following the procedure adopted for
compound 12. ½a 2D5
ꢁ
¼ ꢀ9:0 (c 1, CHCl3); IR (neat): mmax 3453,
2960, 2928, 2879, 1461, 1312, 1109, 1044 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 4.57 (s, 2H), 3.33 (s, 3H), 3.44–3.28 (m, 3H), 1.87–
1.75 (m, 1H), 1.64–1.39 (m, 5H), 0.95 (t, J = 7.4 Hz, 3H), 0.94 (d,
J = 6.8 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 96.5, 75.5, 73.01, 55.1, 37.5, 34.7, 30.6, 27.3, 18.1, 13.8, 10.6;
ESI: m/z = 227 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for
½
a 2D5
ꢁ
¼ ꢀ32:5 (c 2, CHCl3); IR (neat): mmax 3507, 2969, 2935, 2879,
1779, 1694, 1456, 1386, 1212, 1113, 971 cmꢀ1 1H NMR (CDCl3,
;
300 MHz): d 7.37–7.22 (m, 5H), 5.33 (ap ddd, J = 10.5, 6.8, 3.8 Hz,
1H), 4.69 (dq, J = 6.8, 6.8 Hz, 1H), 3.94 (ddd, J = 7.5, 5.3, 2.3 Hz,
1H), 3.35 (dd, J = 12.1, 7.5 Hz, 1H), 3.2 (dd, J = 12.8, 3.8 Hz, 1H),
3.03 (dd, J = 13.6, 10.6 Hz, 1H), 2.88 (d, J = 11.3 Hz, 1H), 2.77–2.59
(br s, OH), 1.65–1.51 (m, 1H), 1.50–1.34 (m, 1H), 1.17 (d,
J = 6.8 Hz, 3H), 0.98 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 201.5, 178.4, 136.3, 129.4, 128.8, 127.2, 72.4, 68.8, 42.1, 36.9,
31.7, 26.5, 10.4, 10.3; ESI: m/z = 346 [M+Na]+. HRMS (ESI):
[M+Na]+ m/z calcd for C16H21NO2NaS2: 346.0911, found: 346.0913.
C11H24O3Na: 227.1623, found: 227.1628.
4.1.10. (((3S,4S,6R)-7-(Methoxymethoxy)-4,6-dimethylheptan-
3-yloxy)methyl)benzene 20
To a stirred suspension of NaH (0.14 g, 5.87 mmol) in dry THF
(10 mL) at 0 °C was added a solution of compound 19 (0.4 g,
1.95 mmol) in dry THF (10 mL). The mixture was refluxed for
30 min and allowed to reach room temperature. Then benzyl bro-

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2071–2079
2077
4.1.13. (2S,3S)-2-Methylpentane-1,3-diol 22
Na2SO4, and concentrated in vacuo. The unstable crude aldehyde
To a solution of 21 (2.7 g, 8.34 mmol) in MeOH (50 mL), NaBH4
(0.79 g, 20.86 mmol) was added at 0 °C and stirred at the same
temperature for 1 h. After the completion of reaction MeOH was
removed under reduced pressure, the reaction mixture was
quenched with saturated NH4Cl solution, extracted with EtOAc,
and washed with brine. The combined organic layers were dried
over anhydrous Na2SO4 and the solvent was removed under re-
duced pressure. The residue was Purified by silica gel column chro-
matography (EtOAc/pet-ether, 7:3) to afford the pure compound
was used immediately for the next reaction.
4.1.17. (2R,3S,4S,5S)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-
5-(benzyloxy)-3-hydroxy-2,4-dimethylheptan-1-one 9
Aldehyde 25 (0.88 g, 4.27 mmol) was converted into compound
9 (1.47 g, 80%) using thiazolidinethione propionate 10 (1.03 g,
3.88 mmol)) following the procedure adopted for the preparation
of compound 21. ½a D25
¼ þ41:0 (c 1.5, CHCl3); IR (neat): mmax
ꢁ
3453, 2868, 2934, 2876, 1695, 1455, 1344, 1257, 1162,
22 (0.86 g, 88%) as viscous liquid. ½a D25
ꢁ
¼ þ1:0 (c 0.5, CHCl3); IR
1030 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 7.37–7.19 (m, 10H),
;
(neat): mmax 3371, 2966, 2932, 2881, 1460, 1027, 967 cmꢀ1
;
1H
5.37 (dddd, J = 10.7, 7.8, 3.9, 0.9 Hz, 1H), 4.78 (dq, J = 6.8, 1.9 Hz,
1H), 4.46 (Abq, J = 18.1, 10.6 Hz, 2H), 4.09 (dd, J = 9.7, 1.9 Hz, 1H),
3.91 (t, J = 6.8 Hz, 1H), 3.33 (dd, J = 10.7, 6.8 Hz, 1H), 3.27 (dd,
J = 12.7, 2.9 Hz, 1H), 3.01 (dd, J = 13.6, 10.7 Hz, 1H), 2.88 (d,
J = 11.7 Hz, 1H), 1.77–1.64 (m, 1H), 1.60–1.48 (m, 2H), 1.18 (d,
J = 6.8 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H); 13C
NMR (CDCl3, 75 MHz): d 201.1, 177.7, 138.5, 136.3, 129.3, 129.1,
128.8, 128.3, 127.4, 127.2, 84.4, 74.7, 71.1, 68.8, 41.6, 36.8, 37.2,
31.4, 23.1, 14.4, 10.1, 7.6; HRMS (ESI): [M+Na]+ m/z calcd for
NMR (CDCl3, 300 MHz): d 3.74–3.66 (m, 3H), 2.48–2.20 (br s, OH,
1H), 1.83–1.71 (m, 1H), 1.57–1.39 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H),
0.91 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 75.8, 66.9,
38.6, 26.8, 10.5, 9.8.
4.1.14. (4S,5S)-4-Ethyl-5-methyl-2-phenyl-1,3-dioxane 23
To a solution of diol 22 (0.8 g, 6.77 mmol) in dry CH2Cl2 (20 mL)
was added the dimethyl acetal of benzaldehyde (1.1 mL,
7.44 mmol) at 0 °C. To the reaction mixture was added a catalytic
amount of pTSA and the reaction mixture was stirred at rt for
2 h. After completion of the reaction, the reaction mixture was
quenched by adding a saturated solution of NaHCO3 at 0 °C and
the product was extracted with CH2Cl2. The combined organic lay-
ers were dried over anhydrous Na2SO4 and the solvent was re-
moved under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/pet-ether, 1:19) to afford
C26H33NO3NaS2: 494.1799, found: 494.1809.
4.1.18. (2S,3R,4S,5S)-5-(Benzyloxy)-2,4-dimethylheptane-1,3-
diol 26
Compound 9 (1.4 g, 2.97 mmol) was converted into compound
26 (0.86 g, 90%) following the procedure adopted for the prepara-
tion of compound 22. ½a D25
¼ þ12:1 (c 2, CHCl3); IR (neat): mmax
ꢁ
3416, 2966, 2932, 2877, 1456, 1417, 1334, 1280, 1059, 971 cmꢀ1
;
pure compound 23 (1.27 g, 91%) as a colorless liquid. ½a D25
ꢁ
¼ ꢀ17:0
1H NMR (CDCl3, 300 MHz): d 7.37–7.26 (m, 5H), 4.56 (ABq,
J = 18.1, 10.6 Hz, 2H), 4.16 (d, J = 5.3 Hz, 1H), 3.77–3.46 (m, 4H),
2.09–1.96 (m, 1H), 1.88–1.68 (m, 2H), 1.61–1.45 (m, 1H), 0.97 (d,
J = 6.8 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13C
NMR (CDCl3, 75 MHz): d 138.4, 128.4, 127.6, 127.5, 84.6, 77.3,
71.4, 66.8, 37.8, 36.7, 23.0, 11.6, 10.2, 7.6; ESI: m/z = 289
[M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C16H26O3Na:
289.1779, found: 289.1787.
(c 0.5, CHCl3); IR (neat): mmax 2966, 2935, 2877, 2848, 1458, 1396,
1370, 1166, 1114, 1073, 1005 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
;
7.37–7.26 (m, 5H), 5.44 (s, 1H), 4.02 (dabq, J = 11.3, 2.3 Hz, 2H),
3.78 (ddd, J = 8.3, 6.0, 2.3 Hz, 1H), 1.76–1.59 (m, 1H), 1.60–1.50
(m, 1H), 1.49–1.38 (m, 1H), 1.16 (d, J = 6.8 Hz, 3H), 0.96 (t,
J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 138.9, 128.6,
128.1, 126.0, 101.8, 81.3, 73.8, 31.3, 25.5, 10.9, 9.6; ESI: m/z = 245
[M+K]+.
4.1.19. (2S,3R,4S,5S)-5-(Benzyloxy)-1-(tert-
4.1.15. (2S,3S)-3-(Benzyloxy)-2-methylpentan-1-ol 24
butyldimethylsilyloxy)-2,4-dimethylheptan-3-ol 27
To a solution of compound 23 (1.22 g, 5.91 mmol) in dry CH2Cl2
(40 mL) was added DIBAL-H (1.7 M in Toluene) at ꢀ15 °C (5.2 mL,
8.87 mmol) and the reaction mixture was stirred at same temper-
ature while monitoring the reaction. After completion of the reac-
tion quenched by the addition of a saturated solution of sodium
potassium tartrate. The mixture was stirred for 2 h at rt. Then
the product was extracted with EtOAc and washed with brine.
The combined organic layers were dried over anhydrous Na2SO4
and concentrated under reduced pressure; the residue was purified
by silica gel column chromatography (EtOAc/pet-ether, 3:7) to fur-
To a stirred solution of diol 26 (0.64 g, 2.40 mmol) and imidaz-
ole (0.49 g, 7.21 mmol) in dry CH2Cl2 (30 mL) was added TBDMS-Cl
(0.36 g, 2.40 mmol) portion wise at 0 °C. The reaction mixture was
stirred at the same temperature for 2 h. The reaction mixture was
quenched with a saturated aqueous solution of NH4Cl and ex-
tracted with CH2Cl2. The extract was washed with water and brine,
dried over anhydrous Na2SO4, the solvent was removed in vacuo
and the residue was purified by silica gel column chromatography
(EtOAc/pet-ether, 1:19) to furnish pure compound 27 (0.868 g, 95%
yield) as a colorless liquid. ½a D25
ꢁ
¼ þ17:6 (c 1, CHCl3); IR (neat): mmax
nish pure compound 24 (1.10 g, 90%) as a clear liquid. ½a D25
ꢁ
¼ ꢀ2:0
3417, 2964, 2932, 2876, 1458, 1381, 1059, 1030, 970 cmꢀ1 1H
;
(c 0.5, CHCl3); IR (neat): mmax 3422, 2966, 2934, 2876, 1457, 1094,
NMR (CDCl3, 300 MHz): d 7.35–7.20 (m, 5H), 4.56 (s, 2H), 3.79–
3.61 (m, 3H), 3.49–3.32 (m, 1H), 2.00–1.84 (m, 1H), 1.83–1.66
(m, 2H), 1.55–1.36 (m, 1H), 1.05–0.86 (m, 18H), 0.06 (s, 6H); 13C
NMR (CDCl3, 75 MHz): d 138.6, 128.3, 127.6, 127.5, 84.3, 77.3,
71.1, 67.4, 37.4, 36.7, 25.8, 25.6, 18.2, 12.0, 10.3, 8.0, ꢀ5.6, ꢀ5.5;
ESI: m/z = 403 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for
1064, 1027 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.37–7.21 (m, 5H),
;
4.55 (s, 2H), 3.63 (dd, J = 10.6, 7.5 Hz, 1H), 3.51 (dd, J = 10.6, 4.5 Hz,
1H), 3.41 (ddd, J = 7.6, 6.0, 3.8 Hz, 1H) 2.10–1.96 (m, 1H), 1.76–1.44
(m, 2H), 0.95 (t, J = 7.5 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d 138.4, 128.3, 127.4, 127.3, 83.5, 71.7, 66.0,
36.6, 22.7, 11.5, 10.5; ESI: m/z = 231 [M+Na]+. HRMS (ESI):
[M+Na]+ m/z calcd for C13H20O2Na: 231.1360, found: 231.1371.
C22H40O3NaSi: 403.2644, found: 403.2632.
4.1.20. O-(2S,3R,4R,5S)-5-(Benzyloxy)-1-(tert-
4.1.16. (2R,3S)-3-(Benzyloxy)-2-methylpentanal 25
butyldimethylsilyloxy)-2,4-dimethylheptan-3-yl S-methyl
carbonodithioate 28
To an ice-cooled solution of 2-iodoxybenzoic acid (1.71 g,
6.10 mmol) in DMSO (3.6 mL, 50.81 mmol) was added a solution
of alcohol 24 (1.06 g, 5.09 mmol) in dry CH2Cl2 (20 mL). The mix-
ture was stirred at room temperature for 2 h and then filtered
through a Celite pad and washed with ether. The combined organic
filtrates were washed with water and brine, dried over anhydrous
Compound 27 (0.8 g, 2.10 mmol) was converted into compound
28 (0.90 g, 91%) following the procedure adopted for the prepara-
tion of compound 16. ½a D25
ꢁ
¼ þ5:1 (c 1, CHCl3); IR (neat): mmax
2925, 2853, 1564, 1494, 1037, 943 cmꢀ1
;
1H NMR (CDCl3,
300 MHz): d 7.35–7.20 (m, 5H), 6.00 (dd, J = 9.2, 3.2 Hz, 1H), 4.43

2078
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2071–2079
(ABq, J = 17.0, 11.5 Hz, 2H), 3.76 (dd, J = 10.2, 6.0 Hz, 1H), 3.43 (dd,
J = 10.0, 7.2 Hz, 1H), 3.23 (ddd, J = 8.7, 5.5, 1.9 Hz, 1H), 2.57 (s, 3H),
2.31–2.11 (m, 2H), 1.87–1.68 (m, 1H), 1.56–1.40 (m, 1H), 1.01 (d,
J = 6.9 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 0.95 (t, J = 6.9 Hz, 3H) 0.91
(s, 9H), 0.06 (s, 6H); 13C NMR (CDCl3, 75 MHz): d 216.3, 139.4,
128.0, 127.4, 127.0, 87.6, 79.7, 71.4, 63.9, 38.1, 37.7, 31.7, 25.9,
23.9, 18.9, 15.1, 10.5, 10.0, ꢀ5.5; ESI: m/z = 493 [M+Na]+.
concentrated under reduced pressure and then anhydrous Et3N
(2 mL), Ac2O (1 mL), and catalytic amount of DMAP were added
to residual 10 at 0 °C. The reaction mixture was stirred for 0.5 h,
and then quenched by adding water, and extracted with diethyl
ether. The combined organic layers were washed with water and
satd NaHCO3 and brine solution and dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure, and the residue
was purified by silica gel column chromatography (EtOAc/pet-
ether, 1:19) to afford compound 30 (0.052 g, 80%) as a colorless li-
4.1.21. ((2R,4S,5S)-5-(Benzyloxy)-2,4-dimethylheptyloxy)(tert-
butyl)dimethylsilane 29
quid. ½a 2D5
ꢁ
¼ ꢀ4:8 (c 1, CHCl3); IR (neat): mmax 2969, 2933, 1732,
Compound 28 (0.85 g, 1.80 mmol) was converted into com-
pound 29 (0.57 g, 87%) following the procedure adopted for the
1459, 1374, 1243, 1021, 963 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
;
4.71 (ddd, J = 8.7, 4.9, 3.9 Hz, 1H), 2.66 (td, J = 13.8, 6.8 Hz, 1H),
2.47 (dq, J = 17.7, 7.4 Hz, 1H), 2.36 (dq, J = 17.7, 7.4 Hz, 1H), 2.05
(s, 3H), 1.78–1.66 (m, 1H), 1.64–1.47 (m, 4H), 1.05 (d, J = 6.8 Hz,
3H), 1.03 (t, J = 7.4 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.88 (t,
J = 7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 214.6, 170.8, 77.6,
43.2, 36.3, 34.2, 33.5, 24.1, 21.0, 17.3, 14.6, 10.1, 7.7; ESI: m/
z = 251 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C13H24O3Na:
251.1623, found: 251.1624.
preparation of compound 6. ½a D25
ꢁ
¼ þ4:1 (c 1, CHCl3); IR (neat):
mmax 2961, 2929, 2874, 1458, 1377, 1091, 1062 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz): d 7.35–7.28 (m, 5H), 4.48 (ABq, J = 11.3 Hz,
2H), 3.42 (dd, J = 9.8, 5.3 Hz, 1H), 3.33 (dd, J = 9.8, 6.0 Hz, 1H),
3.16–3.08 (m, 1H), 1.99–1.87 (m, 1H), 1.70–1.57 (m, 1H), 1.53–
1.40 (m, 4H), 0.98–0.85 (m, 18H), 0.03 (s, 6H); 13C NMR (CDCl3,
75 MHz): d 139.3, 128.2, 127.7, 127.3, 84.5, 71.5, 68.0, 36.8, 33.3,
32.2, 25.9, 22.1, 18.3, 17.9, 15.3, 10.7, -5.3; ESI: m/z = 365
[M+H]+. HRMS (ESI): [M+H]+ m/z calcd for C22H41O2Si: 365.2875,
found: 365.2871.
4.1.25. (3R,4S,6R)-4,6-Dimethyl-7-oxononan-3-yl acetate 3
To a stirred solution of compound 31 (0.1 g, 0.361 mmol) in
benzene (5 mL) was added 10% Pd/C and stirred under an H2 atmo-
sphere for 4 h at room temperature. After completion of the reac-
tion the catalyst was removed by filtration, the solvent
evaporated and then the crude product 10 was used directly for
the next reaction. PPh3 (0.237 g, 0.904 mmol) and acetic acid
(0.207 mL, 3.617 mmol) were added to a solution of the above
compound 10 in THF (5 mL). DEAD (0.143 mL, 0.723 mmol) was
added dropwise to it at 0 °C. The mixture was stirred at room tem-
perature for 1 h. The solvent was removed under reduced pressure,
and the mixture was purified by silica gel column chromatography
(EtOAc/pet-ether, 1:19) to afford pure compound 3 (0.049 g, 60%)
4.1.22. (2R,4S,5S)-5-(Benzyloxy)-2,4-dimethylheptana1 30
Compound 5 (0.6 g, 2.39 mmol) was converted into compound
30 following the procedure adopted for the preparation of com-
pound 25. The unstable crude aldehyde was used immediately in
the next reaction.
4.1.23. (4R,6S,7S)-7-(Benzyloxy)-4,6-dimethylnonan-3-one 31
To a suspension of Mg (0.120 g, 5.03 mmol) in dry THF (10 mL),
EtBr (0.388 g, 5.032 mmol) was added dropwise under N2 atmo-
sphere at 0 °C. It was allowed to stir for 30 min, at room tempera-
ture. To this Grignard reagent, aldehyde 30 (0.250 g, 1.006 mmol)
in dry THF (10 mL) was added at 0 °C. After completion of the reac-
tion the reaction mixture was quenched with saturated aqueous
NH4Cl solution, and then filtered through a Celite pad and washed
with ethyl acetate. The filtrate was dried over anhydrous Na2SO4,
and concentrated under reduced pressure. Purification of the crude
product by silica gel column chromatography (EtOAc/pet-ether,
1:9) afforded alcohol as a diastereomeric mixture (0.252 g, 90%).
The alcohol (0.25 g, 0.897 mmol) in dry CH2Cl2 (10 mL) was added
dropwise at 0 °C to an ice-cooled solution of 2-iodoxybenzoic acid
(0.301 g, 1.077 mmol) in DMSO (0.382 mL, 5.60 mmol). The mix-
ture was stirred at room temperature for 2 h and then filtered
through a Celite pad and washed with ether. The combined organic
filtrates were washed with water and brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude product was purified
by column chromatography (EtOAc/pet-ether, 1:19) to afford the
as a pale yellow liquid. ½a D25
ꢁ
¼ þ12:5 (c 1, CHCl3); IR (neat): mmax
2969, 2933, 1732, 1459, 1374, 1243, 1021, 963 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz): d 4.63 (dt, J = 7.9, 4.9 Hz, 1H), 2.62 (ddq,
J = 8.9, 6.9, 4.9 Hz, 1H), 2.47 (dq, J = 17.8, 6.9 Hz, 1H), 2.39 (dq,
J = 17.8, 6.9 Hz, 1H), 2.04 (s, 3H), 1.86–1.78 (m, 1H), 1.63–1.46
(m, 4H), 1.09 (d, J = 6.9 Hz, 3H), 1.04 (t, J = 6.9 Hz, 3H), 0.87 (d,
J = 6.9 Hz, 3H), 0.86 (t, J = 6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 214.9, 170.9, 78.8, 43.7, 35.3, 34.0, 33.9, 23.2, 21.0, 18.0, 15.7,
9.9, 7.7; ESI: m/z = 251 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd
for C13H24O3Na: 251.1623, found: 251.1613.
4.1.26. (3R,5S,6S)-6-(Benzyloxy)-3,5-dimethyloctan-2-one 32
Aldehyde 30 (0.25 g, 1.006 mmol) was converted into com-
pound 32 (0.205 g, 90%) using MeI (0.313 g, 5.032 mmol) and dry
ether as a solvent for Grignard reaction following the procedure
adopted for the preparation of compound 31. ½a D25
¼ ꢀ35:0 (c 0.5,
ꢁ
pure compound 31 (0.228 g, 92%) as
¼ ꢀ18:0 (c 0.5, CHCl3); IR (neat): mmax 2967, 2934, 2876,
1711, 1458, 1376, 1099, 1067 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
a
colorless liquid.
CHCl3); IR (neat): mmax 2966, 2930, 2875, 1710, 1457, 1373,
½
a 2D5
ꢁ
1098 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.33–7.18 (m, 5H), 4.48
;
;
(s, 2H), 3.12 (dt, J = 8.1, 4.5 Hz, 1H), 2.56 (ddq, J = 13.4, 9.6,
6.4 Hz, 1H), 2.05 (s, 3H), 1.94–1.82 (m, 1H), 1.63–1.42 (m, 4H)
1.08 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.88 (d, J = 6.6 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d 213.1, 139.0, 128.2, 127.7,
127.3, 84.2, 71.6, 45.0, 35.9, 32.8, 27.6, 22.9, 17.4, 15.0, 10.5; ESI:
m/z = 285 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for
7.32–7.18 (m, 5H), 4.48 (s, 2H), 3.16–3.05 (m, 1H), 2.68–2.53 (m,
1H), 2.38 (q, J = 14.4, 7.6 Hz, 2H) 1.95–1.82 (m, 1H), 1.71–1.41
(m, 3H), 1.34–1.20 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H), 1.01 (t,
J = 7.6 Hz, 3H), 0.91 (t, J = 7.6 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H); 13C
NMR (CDCl3, 75 MHz): d 215.5, 139.0, 128.2, 127.7, 127.3, 84.3,
71.6, 43.9, 36.2, 33.9, 32.8, 22.9, 17.7, 15.0, 10.4, 7.7; ESI: m/
z = 299 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd for C18H28O2Na:
299.1987, found: 299.1986.
C17H26O2Na: 285.1830, found: 285.1834.
4.1.27. (3S,4S,6R)-4,6-Dimethyl-7-oxooctan-3-yl acetate 4’
Compound 32 (0.107 g, 0.266 mmol) was converted into com-
pound 40 (0.046 g, 81%) following the procedure adopted for the
4.1.24. (3S,4S,6R)-4,6-Dimethyl-7-oxononan-3-yl acetate 3’
To a stirred solution of 31 (0.08 g, 0.289 mmol) in anhydrous
benzene (5 mL) was added catalytic amount of 10% palladium ad-
sorbed on carbon and stirred under an H2 atmosphere for 4 h. The
reaction mixture was filtered through Celite and the filtrate was
preparation of compound 30. ½a D25
ꢁ
¼ ꢀ30:1 (c 1, CHCl3); IR (neat):
mmax 2967, 2929, 1733, 1459, 1372, 1243, 1020, 960 cmꢀ1
;
1H
NMR (CDCl3, 400 MHz): d 4.73 (dt, J = 8.3, 5.3 Hz, 1H), 2.64 (sextet,
J = 6.8 Hz, 1H), 2.10 (s, 3H), 2.06 (s, 3H) 1.72 (ddd, J = 13.6, 7.5,

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 2071–2079
2079
6.0 Hz, 1H), 1.66–1.45 (m, 3H), 1.08 (d, J = 7.5 Hz, 3H), 1.10–0.99
(m, 1H), 0.89 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d 212.4, 170.9, 77.6, 44.3, 36.1, 33.4, 27.9, 24.1,
21.0, 16.9, 14.4, 10.1; ESI: m/z = 237 [M+Na]+. HRMS (ESI):
[M+Na]+ m/z calcd for C12H22O3Na: 237.1466, found: 237.1456.
port by King Saud University for Global Research Network for Or-
ganic Synthesis (GRNOS).
References
1. Nishidha, R.; Fukami, H. Mem. Coll. Agric., Kyoto Univ. 1983, 122, 1–24.
2. Riley, R. G.; Silverstein, R. M.; Moser, J. C. Science 1974, 183, 760–762.
3. Rodin, J. O.; Silverstein, R. M.; Burkhoder, W. E.; Gorman, J. E. Science 1969, 165,
904–906.
4. Masuda, Y.; Fujitha, K.; Mori, K. Biosci. Biotechnol. Biochem. 2003, 67, 1744–
1750.
5. (a) Yadav, J. S.; Rao, C. S.; Chandrasekhar, S.; Rama Rao, A. V. Tetrahedron Lett.
1995, 36, 7717–7720; (b) Yadav, J. S.; Abraham, S.; Reddy, M. M.; Sabitha, G.;
Sanker, A. R.; Kunwar, A. C. Tetrahedron Lett. 2001, 42, 4713–4716; (c) Yadav, J.
S.; Reddy, K. B.; Sabitha, G. Tetrahedron Lett. 2004, 45, 6475–6476; (d) Yadav, J.
S.; Reddy, K. B.; Sabitha, G. Tetrahedron 2008, 64, 1971; (e) Sabitha, G.; Yadagiri,
K.; Chandrashekhar, G.; Yadav, J. S. Synthesis 2010, 4307–4311; (f) Yadav, J. S.;
Yadagiri, K.; Madhuri, Ch.; Sabitha, G. Tetrahedron Lett. 2011, 52, 4269–4272;
(g) Sabitha, G.; Yadagiri, K.; Bhikshapathi, M.; Chandrashekhar, G.; Yadav, J. S.
Tetrahedron: Asymmetry 2010, 21, 2524–2529.
6. Stork, G.; Takahashi, J. J. Am. Chem. Soc. 1977, 99, 1275–1276.
7. Phillips, K. D.; Zemlicka, J.; Horowitz, J. P. Carbohydr. Res. 1973, 30, 281–286.
8. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc. Perkin Trans. 1 1975, 1574–1585.
9. Ramana, C. V.; Srinivas, B.; Puranik, V. G.; Gurjar, M. K. J. Org. Chem. 2005, 70,
8216–8219.
4.1.28. (3R,4S,6R)-4,6-Dimethyl-7-oxooctan-3-yl acetate 4
Compound 32 (0.1 g, 0.381 mmol) was converted into com-
pound 4 (0.048 g, 59%) following the procedure adopted for the
preparation of compound 3. ½a D25
ꢁ
¼ þ19:8 (c 1, CHCl3); IR (neat):
mmax 2967, 2929, 1733, 1459, 1372, 1243, 1020, 960 cmꢀ1
;
1H
NMR (CDCl3, 400 MHz): d 4.64 (dt, J = 7.9, 4.9 Hz, 1H), 2.59 (ddq,
J = 9.8, 6.9, 4.9 Hz, 1H), 2.12 (s, 3H), 2.05 (s, 3H) 1.84–1.77 (m,
1H), 1.67–1.48 (m, 3H), 1.12 (d, J = 6.9 Hz, 3H), 1.10–1.02 (m,
1H), 0.87 (d, J = 6.9 Hz, 3H), 0.87 (t, J = 6.9 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 212.4, 171.0, 78.8, 44.8, 35.3, 33.9, 27.7, 23.2, 21.0, 17.7,
15.6, 9.9; ESI: m/z = 237 [M+Na]+. HRMS (ESI): [M+Na]+ m/z calcd
for C12H22O3Na: 237.1466, found: 237.1458.
Acknowledgments
10. (a) Crimins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775; (b) Crimins, M. T.; King,
B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894.
11. Schreiber, S. L.; Wang, Z.; Schulte, G. Tetrahedron Lett. 1988, 29, 4085–4088.
12. Sánta, Z.; Nagy, J.; Nyitrai, J. Tetrahedron: Asymmetry 2006, 17, 3111–3127.
Ch. S. thanks UGC-New Delhi, and Ch. M. thanks CSIR New Delhi
for the award of Fellowships. J.S.Y. acknowledges the partial sup-