Proline-catalyzed stereoselective synthesis of natural and unnatural nocardiolactone

Article abstract of DOI:10.1016/j.tet.2008.04.062

A concise diastereo and enantioselective synthesis of natural and unnatural nocardiolactone is accomplished by proline-catalyzed crossed-aldol reaction as the key step.

Full text of DOI:10.1016/j.tet.2008.04.062

Tetrahedron 64 (2008) 5861–5865
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Proline-catalyzed stereoselective synthesis of natural and unnatural
nocardiolactone
*
G. Kumaraswamy , B. Markondaiah
Organic Division III, Fine Chemicals Laboratory, Indian Institute of Chemical Technology, Hyderabad-500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise diastereo and enantioselective synthesis of natural and unnatural nocardiolactone is accom-
plished by proline-catalyzed crossed-aldol reaction as the key step.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 14 February 2008
Received in revised form 14 April 2008
Accepted 16 April 2008
Available online 18 April 2008
Keywords:
Nocardiolactone
Unnatural nocardiolactone
trans-b-Lactone
Proline
Glyceraldehyde acetonide
Aldolization
1. Introduction
2. Results and discussion
Disubstituted trans-
b
-lactones are considered to be pivotal
Our continuing interest in the development of enantioselective
synthetic routes9 for the disubstituted trans-
-lactones prompted
us to apply S-proline-catalyzed crossed-aldol reaction to install the
two stereocenters of the trans- -lactone in a highly diastereo and
enantioselective manner. Our approach toward the synthesis of
nocardiolactone 1a is shown in Scheme 1.
structural motif for many natural and unnatural molecules such as
ebelactones, lipstatin, panclicins, tetrahydrolipstatin, 1233A,
belactosins, and nocardiolactone.1 These molecules display signif-
icant biological activity such as antibiotic and antiobesity.1c,d Ad-
b
b
ditionally, the simplified disubstituted trans-b-lactones potentially
act as inhibitors of several enzymes including proteases,2 HMG Co-
We have initiated S-proline (10 mol %) catalyzed crossed-aldol
reaction between eicosanal 2 and glyceraldehyde acetonide 3,
A synthase,3 and esterase.4 Nocardiolactone 1a, a trans-disposed
disubstituted
b-lactone was isolated by Mikami et al. from patho-
which in turn was prepared from D-mannitol. After considerable
genic Nocardia strains and found to exhibit narrow spectrum
activity against Gram-positive bacteria, Bacillus subtilis ATCC
66335 (Fig. 1). Nocardiolactone 1a has been synthesized for the
first time through an enantioselective route based on Crimmins
aldolization followed by DBU-mediated lactonization thereby
experimentation, the reaction was carried out with 10 mol % of S-
proline and 1 equiv of 2 and 2 equiv of 3 in dry DMF at ambient
O
O
establishing the absolute configuration of the trans-
b-lactone
as S,S.6
Recently, impressive organocatalytic routes have been de-
veloped for the disubstituted cis-
-lactones in high enantiopurity.7
The cis- -lactones were also epimerized to thermodynamically
favored trans-
-lactones under strong basic conditions.8
1a
b
b
O
O
b
1b
* Corresponding author. Tel.: þ91 40 27193154; fax: þ91 40 27193275.
E-mail address: gkswamy_iict@yahoo.co.in (G. Kumaraswamy).
Figure 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.062

5862
G. Kumaraswamy, B. Markondaiah / Tetrahedron 64 (2008) 5861–5865
O
O
OH
O
HO
C16H33
10a
1a
OBn
OH
OBn
O
O
H
O
C16H33
C16H33
8a
4a
Scheme 1.
temperature stirring for 24 h, which lead to the anti-aldol product
4a in 70% isolated yield (dr¼9:1).10 Interestingly, we were also able
to show that by changing (S)- to (R)-proline (10 mol %), under
otherwise identical conditions, the aldol product 4b was received in
slightly less yields with same diastereoselectivity. The result
indicates that there is a negligible matched or mismatched effect
on the outcome diastereoselectivity of product 4a and 4b.
Furthermore, the reagent plays a decisive role on the anti-aldol
diastereoselectivity, which is also consistent with similar proline-
catalyzed reactions.11
oxidation of the resulting aldehyde employing perchlorite/dihy-
drogen orthophosphate furnished the
-hydroxy acid12b 10a in 85%
yield. The -hydroxy acid 10a was lactonized to bis(2-oxo-3-oxa-
zolidinyl)phosphinic chloride (BOPCl) and Et3N as base lead to the
title compound 1a in 72% yield (Scheme 2). The spectral and ana-
lytical data of 1a were in full agreement with the reported
b
b
25
25
data ([
a]
ꢀ12.6 (c .01, CHCl3); lit.5
[a
]
ꢀ12.7 (c 2.5, CHCl3)).5
D
D
The unnatural nocardiolactone 1b was synthesized starting from
4b following the same reaction sequence of 1a. The optical rotation
of 1b found to be similar in magnitude but opposite in sign to that
of 1a.
The subsequent reduction of 4a using NaBH4/MeOH resulted to
the 1,3-diol 5a in 85% yield. The 1,3-hydroxyl groups were protected
as its benzyl ethers using NaH/BnBr in the presence of catalytic
amount of TBAI. The acetonide was deprotected with PTSA/
(MeOH:THF) (9:1) to give 1,2-diol, followed by oxidative cleavage of
the corresponding 1,2-diol using sodium metaperiodate in THF/H2O
(9:1) resulting in aldehyde 7a in 88% yield. This aldehyde was
subjected to Wittig reaction using C12Hþ25PPh3Brꢀ and n-BuLi in THF
to give the olefin (E/Z, 2:8) 8a in 70% yield. Hydrogenation of 8a
with 10% Pd–C/H2 in MeOH/EtOAc (6:4) gave the corresponding
1,3-diol 9a in 92% yield.
3. Conclusion
In conclusion, we have developed the organocatalytic route for
the total synthesis of natural and unnatural nocardiolactone mol-
ecules. To the best of our knowledge this is the first catalytic route
to nocardiolactone 1a. Significantly, the chirality of the
moiety was installed with inexpensive naturally occurring amino-
acid such as -proline. Application of this novel methodology to
synthesize various disubstituted trans-
b-lactone
L
The TEMPO catalyzed chemoselective oxidation12a of 9a with
bis(acetoxy)iodobenzene (BAIB) in CH2Cl2 followed by further
b
-lactones in order to study
their activity profiles is under progress.
OH
OH
O
CHO
(S)-Proline(10mol%)
NaBH4, MeOH
C17H35
O
O
H
HO
C16H33
OHC
0 °C - rt., 2 h
O
O
C16H33
O
2
O
3
5a, 85%
4a, 70%
DMF, 24 h, rt
OBn
OBn
OBn
OBn
O
OBn
i) PTSA, MeOH:THF(9:1)
rt., 2 h,
NaH, BnBr, cat.TBAI
THF, 0 °C to reflux
H
O
ii) NaIO4, THF:H2O(9:1)
rt., 3 h
O
C16H33
C16H33
12 h
7a, 88%
(after two steps)
6a, 82%
OH
OH
OBn
n-BuLi, THF
C12H25+PPh3 Br-
H2, 10% Pd-C
-18 °C - rt., 6 h
MeOH:EtOAc
(6:4)
C16H33
C16H33
9a, 92%
8a (E / Z, 2 : 8), 70%
OH
O
i) TEMPO, BAIB
CH2Cl2, rt., 2 h
ii) NaClO2, NaH2PO4
t-BuOH, 23 °C, 2 h
BOPCl, Et3N
1a
HO
C16H33
CH2Cl2, 23 °C, 2 h
72%
10a, 85%
Scheme 2.

G. Kumaraswamy, B. Markondaiah / Tetrahedron 64 (2008) 5861–5865
5863
4. Experimental section
4.1. General
4.4. Typical procedure for the reduction: (1R,2R)-1-((R)-2,2-
dimethyl-1,3-dioxolan-4yl)-2-octadecylpropane-1,3-diol, 5a
Sodium borohydride (0.67 g, 17.6 mmol) was added to the aldol
product 3a (5 g, 11.73 mmol) dissolved in methanol (100 mL). The
resulting reaction mixture was stirred at rt, for 1.5 h. Then the
MeOH was removed from the reaction mixture and quenched with
saturated NH4Cl solution at 0 ꢁC. The reaction mixture was
extracted with ethyl acetate (2ꢂ50 mL). The organic extracts were
washed with water (1ꢂ20 mL), followed by brine (1ꢂ20 mL), dried,
and concentrated under reduced pressure. The residue was purified
by column chromatography to give the corresponding 1,3-diol 5a
Solvents were dried over standard drying agents and freshly
distilled prior to use. Chemicals were purchased and used with-
out further purification. All column chromatographic separations
were performed using silica gel (Acme’s, 60–120 mesh). Organic
solutions were dried over anhydrous Na2SO4 and concentrated
below 40 ꢁC in vacuo. 1H NMR (200 and 300 MHz) and 13C NMR
(50 and 75 MHz) spectra were measured with a Varian Gemini
FT-200 MHz spectrometer and Bruker Avance 300 MHz, with
tetramethylsilane as an internal standard for solutions in deu-
teriochloroform. J values are given in hertz. IR spectra were
recorded on a Perkin–Elmer IR-683 spectrophotometer. Optical
rotations were measured with HORIBA SEPA-300 high sensitive
polarimeter at 25 ꢁC. Mass spectra were recorded on CEC-21-
11013 or Finnigan Mat 1210 double focusing mass spectrometer
operating at a direct inlet system or LC/MSD Trap SL (Agilent
Technologies).
(4.25 g, 85% yield) as a colorless solid. Mp 55–57 ꢁC; TLC, Rf 0.29
25
(20% EtOAc/hexane); [
CDCl3):
a]
ꢀ13.5 (c 0.01, CHCl3); 1H NMR (300 MHz,
D
d
4.21 (dd, J¼12.0, 6.8 Hz, 1H), 4.0 (dd, J¼8.3, 6.8 Hz, 1H),
3.76–3.70 (m, 2H), 3.64–3.50 (m, 2H), 2.76–2.70 (m, 1H), 2.59 (d,
J¼5.3 Hz, 1H), 1.68–1.62 (m, 1H), 1.43 (s, 3H), 1.37 (s, 3H), 1.31–1.21
(m, 34H), 0.88 (t, J¼6.0 Hz, 3H); 13C NMR (75 MHz):
d 109.5, 77.5,
74.5, 66.4, 62.8, 43.0, 31.9, 29.8, 29.7, 29.5, 29.3, 28.9, 27.2, 26.5, 25.4,
22.6, 14.0; IR (KBr): 3335, 2917, 1052, 849, 753 cmꢀ1; MS (LC): m/z
451 [MþNa]þ; ESI-HRMS: m/z calcd for C26H52O4Na [MþNa]þ
451.3763; found 451.3744.
4.2. Typical procedure for the aldol reaction: (S)-2-((R)-
hydroxy ((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-
icosanal, 4a
4.5. (1S,2S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4yl)-2-octa-
decylpropane-1,3-diol, 5b
The compound 5b (4.2 g, 84% yield) as a colorless solid, mp 54–
A
DMF solution of glyceraldehyde acetonide
3 (4.3 g,
56 ꢁC, was synthesized from 4b (5 g, 11.73 mmol) according to
33.72 mmol) was treated with successively -proline (0.194 g,
L
25
typical procedure 5a. TLC, Rf 0.29 (20% EtOAc/hexane); [
a
]
D
þ14.0
1.68 mmol) and 1-eicosanal 2 (5 g, 16.86 mmol). The resulting
reaction mixture was stirred at rt for 24 h, and then the reaction
mixture was diluted with diethyl ether (1ꢂ125 mL). The ether
layer was washed successively with water (2ꢂ100 mL) and brine
(2ꢂ100 mL). The combined aqueous layers were extracted with
ethyl acetate (4ꢂ150 mL). The combined ether and ethyl acetate
layers were dried and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography to give
(c 0.018, CHCl3); 1H NMR (300 MHz, CDCl3):
d
4.13 (dd, J¼12.8,
6.0 Hz, 1H), 4.03 (dd, J¼8.3, 6.0 Hz, 1H), 3.94–3.86 (m, 2H), 3.70–
3.64 (m, 2H), 1.63–1.56 (m, 1H), 1.39 (s, 3H), 1.34 (s, 3H), 1.32–1.24
(m, 34H), 0.88 (t, J¼6.8 Hz, 3H); 13C NMR (75 MHz):
d 109.1, 76.3,
75.2, 66.0, 64.0, 41.1, 31.9, 29.8, 29.7, 29.5, 29.3, 28.0, 27.1, 26.6, 25.2,
22.6, 14.1; IR (KBr): 3335, 2917, 2849, 1461, 1029, 789 cmꢀ1; MS
(LC): m/z 451 [MþNa]þ; ESI-HRMS: m/z calcd for C26H52O4Na
[MþNa]þ 451.3763; found 451.3773.
the
Mp 49–51 ꢁC; TLC, Rf 0.56 (30% EtOAc/hexane); [
0.012, CHCl3); 1H NMR (300 MHz, CDCl3):
b-hydroxy aldehyde 4a (5 g, 70% yield) as a colorless solid.
25
a]
þ3.5 (c
D
d
9.72 (d, J¼3.8 Hz, 1H),
4.6. Typical procedure for the benzylation: (R)-4-((1R,2R)-1-
(benzyloxy)-2-((benzyloxy)methyl)icosyl)-2,2-dimethyl-1,3-
dioxolane, 6a
4.12 (ddd, J¼11.3, 6.8, 4.5 Hz, 1H), 4.03 (dd, J¼8.3, 6.8 Hz, 1H), 3.80
(dd, J¼7.5, 6.0 Hz, 1H), 3.72–3.65 (m, 1H), 2.42–2.35 (m, 1H),
2.30–2.25 (m, 1H), 1.84–1.74 (m, 1H), 1.65–1.55 (m, 1H), 1.42 (s,
3H), 1.35 (s, 3H), 1.30–1.22 (m, 32H), 0.88 (t, J¼6.0 Hz, 3H); 13C
To a suspension of NaH (60%, 0.82 g, 20.44 mmol) in dry THF
(20 mL) was added dropwise a solution of 1,3-diol 5a (3.5 g,
8.18 mmol) in THF (25 mL) at 0 ꢁC. To this reaction mixture TBAI
(0.15 g) and benzyl bromide (2.43 mL, 20.44 mmol) were added
subsequently and stirring was continued for 2 h at the same tem-
perature and 12 h at reflux temperature. The reaction mixture was
quenched by saturated NH4Cl solution at 0 ꢁC. The reaction mixture
was extracted with ethyl acetate (2ꢂ50 mL). The organic extracts
were washed with water (1ꢂ20 mL), followed by brine (1ꢂ20 mL),
dried, and concentrated under reduced pressure. The residue was
purified by column chromatography to give the benzylated product
NMR (75 MHz):
d 204.6, 109.7, 76.6, 72.1, 65.8, 55.0, 31.9, 29.6,
29.5, 29.2, 27.0, 26.4, 26.3, 25.1, 22.6, 14.0; IR (KBr): 3421, 2920,
2851, 1721, 1463, 1211, 849 cmꢀ1; MS (LC): m/z 449 [MþNa]þ; ESI-
HRMS: m/z calcd for C26H50O4Na [MþNa]þ 449.3606; found
449.3626.
4.3. (R)-2-((S)-Hydroxy ((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)methyl)icosanal, 4b
The aldol product 4b (4.88 g, 68% yield) as a colorless solid, mp
6a (4 g, 82% yield) as a colorless oily liquid. TLC, Rf 0.59 (10% EtOAc/
þ5.9 (c 0.0135, CHCl3); 1H NMR (300 MHz, CDCl3):
25
47–49 ꢁC, was synthesized from 2 (5 g, 16.86 mmol) according to
hexane). [
a]
D
25
typical procedure 4a. TLC, Rf 0.55 (30% EtOAc/hexane); [
a]
þ12.3
d
7.33–7.25 (m, 10H), 4.87 (d, J¼11.3 Hz, 1H), 4.57 (d, J¼11.3 Hz, 1H),
D
(c 0.038, CHCl3); 1H NMR (300 MHz, CDCl3):
d
9.73 (d, J¼2.7 Hz,1H),
4.54 (s, 2H), 4.48–4.39 (m, 1H), 4.01–3.96 (dd, J¼7.5, 6.0 Hz, 1H),
3.66–3.60 (dd, J¼9.0, 7.5 Hz, 1H), 3.50–3.40 (m, 2H), 3.32–3.27 (dd,
J¼9.8, 5.3 Hz, 1H), 1.55–1.50 (m, 1H), 1.43 (s, 3H), 1.34 (s, 3H), 1.30–
4.11–4.0 (m, 2H), 3.90–3.81 (m, 1H), 3.68–3.64 (m, 1H), 2.62–2.56
(m,1H), 2.52–2.45 (m,1H),1.81–1.70 (m,1H),1.64–1.55 (m,1H),1.37
(s, 3H), 1.31 (s, 3H), 1.30–1.20 (m, 32H), 0.88 (t, J¼6.8 Hz, 3H); 13C
1.17 (m, 34H), 0.88 (t, J¼6.0 Hz, 3H); 13C NMR (75 MHz):
d 139.2,
NMR (75 MHz):
d
204.5, 108.9, 76.2, 72.0, 66.0, 52.6, 31.3, 29.1, 28.9,
138.5, 128.7, 128.1, 127.7, 127.4, 127.2, 109.0, 81.0, 79.3, 73.9, 73.1,
70.2, 66.6, 41.8, 32.9, 29.7, 29.6, 29.5, 29.4, 29.3, 27.5, 26.8, 25.7, 22.6,
14.1; IR (KBr): 2924, 2853, 1457, 1372, 1211, 1092, 753 cmꢀ1; MS
(LC): m/z 631 [MþNa]þ; ESI-HRMS: m/z calcd for C40H64O4Na
[MþNa]þ 631.4702; found 631.4705.
28.7, 26.7, 26.0, 25.4, 24.5, 22.0, 13.5; IR (KBr): 3421, 2920, 2851,
2721, 1708, 1463, 1214, 849 cmꢀ1; MS (LC): m/z 449 [MþNa]þ; ESI-
HRMS: m/z calcd for C26H50O4Na [MþNa]þ 449.3606; found
449.3612.

5864
G. Kumaraswamy, B. Markondaiah / Tetrahedron 64 (2008) 5861–5865
4.7. (R)-4-((1S,2S)-1-(Benzyloxy)-2-((benzyloxy)methyl)-
icosyl)-2,2-dimethyl-1,3-dioxolane, 6b
n-butyl lithium (4.24 mL, 6.71 mmol, 1.6 M, color change from
yellow to orange red was observed). Reaction mixture was stirred at
this temperature for 45 min. A solution of aldehyde 7a (2 g,
3.73 mmol) in anhydrous THF (30 mL) was added dropwise at the
same temperature then the reaction mixture was allowed to warm
up to rt. After 12 h, the reaction mixture was quenched with sat-
urated solution of NH4Cl (10 mL). The solvent was removed under
reduced pressure and the residue was dissolved in EtOAc (20 mL),
washed with water (10 mL) and then with saturated brine solution
(5 mL). The organic phase was dried and concentrated under re-
duced pressure. The residue was purified by column chromatog-
The compound 6b (4.1 g, 84% yield) as a colorless oily liquid was
synthesized from 5b (3.5 g, 8.18 mmol) according to typical pro-
25
cedure 6a. TLC, Rf 0.58 (10% EtOAc/hexane). [
a
]
D
þ10.2 (c 0.014,
CHCl3); 1H NMR (300 MHz, CDCl3):
d
7.30–7.24 (m, 10H), 4.66 (d,
J¼11.7 Hz, 1H), 4.53 (d, J¼11.7 Hz, 1H), 4.43 (s, 2H), 4.25–4.16 (m,
1H), 3.96 (dd, J¼8.0, 6.6 Hz, 1H), 3.85 (dd, J¼8.0, 7.3 Hz, 1H), 3.68–
3.59 (m, 1H), 3.57–3.34 (m, 2H), 1.92–1.84 (m, 1H), 1.37 (s, 3H), 1.30
(s, 3H), 1.29–1.19 (m, 34H), 0.88 (t, J¼5.9 Hz, 3H); 13C NMR
(75 MHz):
d
138.5, 138.4, 128.0, 127.5, 127.3, 127.2, 127.0, 108.5, 79.6,
raphy to give the olefin (E/Z, 2:8) 8a (1.8 g, 70% yield) as a colorless
25
77.2, 73.8, 72.9, 70.1, 66.3, 41.2, 31.9, 29.8, 29.6, 29.5, 29.3, 28.3, 27.5,
26.5, 25.2, 22.7, 14.1; IR (KBr): 2928, 2853, 1494, 1371, 1251, 1082,
852 cmꢀ1; MS (LC): m/z 631 [MþNa]þ; ESI-HRMS: m/z calcd for
liquid. TLC, Rf 0.51 (5% EtOAc/hexane). [
a]
þ8.5 (c 0.001, CHCl3);
D
1H NMR (300 MHz, CDCl3):
d
7.28–7.18 (m, 10H), 5.67–5.60 (m, 1H),
5.31–5.24 (m,1H), 4.52 (d, J¼12.0 Hz,1H), 4.43 (s, 2H), 4.26–4.19 (m,
2H), 3.59–3.54 (m, 1H), 3.44–3.40 (m, 1H), 2.12–1.93 (m, 2H), 1.70–
1.67 (m, 1H), 1.53–1.13 (m, 52H), 0.88 (t, J¼6.0 Hz, 6H); 13C NMR
C
40H64O4Na [MþNa]þ 631.4702; found 631.4717.
4.8. Typical procedure for the oxidation reaction: (2R,3R)-2-
(75 MHz, CDCl3): d 133.8, 133.6, 128.7, 128.4, 128.1, 127.5, 127.3,
(benzyloxy)-3-((benzyloxy)methyl)henicosanal, 7a
127.2, 79.7, 74.4, 72.9, 69.5, 43.8, 31.9, 29.9, 29.7, 29.5, 29.3, 27.9,
27.4, 27.2, 22.6, 14.1; IR (KBr): 2925, 2854, 1465, 1149, 1036,
920 cmꢀ1; MS (LC): m/z 711 [MþNa]þ; ESI-HRMS: m/z calcd for
A solution of benzylproduct 6a (4 g, 6.57 mmol) in 50 mL MeOH/
THF (9:1) was treated with catalytic amount of PTSA. After 2 h, the
resulting reaction mixture was concentrated under reduced pres-
sure. Then the resulting residue was dissolved in EtOAc (20 mL)
then washed with saturated sodium bicarbonate solution
(2ꢂ15 mL). The organic phase was dried and concentrated under
reduced pressure to give the crude 1,2-diol, it was used directly for
further reaction. NaIO4 (2.63 g, 12.32 mmol) was added to the 1,2-
diol dissolved in 50 mL THF/H2O (9:1). The resulting reaction
mixture was stirred at rt, for 1.5 h. Then the THF was removed from
the reaction mixture and the aqueous layer was extracted with
EtOAc (3ꢂ25 mL). The combined organic phases were dried and
concentrated under reduced pressure. The residue was purified by
C
48H80O2Na [MþNa]þ 711.6056; found 711.6044.
4.11. 1-(((R)-2-((S, E/Z)-1-(Benzyloxy)tetradec-2-enyl)icosyl-
oxy)methyl)benzene, 8b
The olefin (E/Z, 2:8) 8b (1.8 g, 70% yield) as a colorless liquid was
prepared from 7b (2 g, 3.73 mmol) according to typical procedure
25
8a. TLC, Rf 0.51 (5% EtOAc/hexane); [
NMR (300 MHz, CDCl3):
a]
ꢀ2.27 (c 0.011, CHCl3); 1H
D
d
7.28–7.18 (m, 10H), 5.7–5.6 (m, 1H), 5.4–
5.27 (m, 1H), 4.55 (d, J¼12.1 Hz, 1H), 4.46 (s, 2H), 4.30–4.22 (m, 2H),
3.62–3.55 (m, 1H), 3.47–3.40 (m, 1H), 2.12–1.97 (m, 2H), 1.80–1.72
(m, 1H), 1.45–1.22 (m, 52H), 0.91 (t, J¼6.0 Hz, 6H); 13C NMR
column chromatography to give the aldehyde 7a (2.87 g, 88% yield)
(75 MHz, CDCl3): d 137.2, 132.1, 131.9, 128.7, 128.3, 128.2, 127.8,
25
as a colorless liquid. TLC, Rf 0.50 (10% EtOAc/hexane). [
a]
þ11.2 (c
127.4, 127.2, 79.5, 74.4, 72.9, 69.9, 44.1, 32.3, 30.3, 29.4, 27.8, 27.5,
27.3, 22.6,14.1; IR (KBr): 2927, 2824,1439,1152,1029, 788 cmꢀ1; MS
(LC): m/z 711 [MþNa]þ.
D
0.026, CHCl3); 1H NMR (300 MHz, CDCl3):
d
9.7 (br s, 1H), 7.30–7.23
(m, 10H), 4.77 (d, J¼11.3 Hz, 1H), 4.46 (d, J¼11.3 Hz, 1H), 4.4 (s, 2H),
3.70–3.68 (m, 1H), 3.56–3.50 (m, 1H), 3.40–3.31 (m, 1H), 2.2–2.1 (m,
1H), 1.33–1.20 (m, 34H), 0.88 (t, J¼6.0 Hz, 3H); 13C NMR (75 MHz):
4.12. Typical procedure for the hydrogenation reaction:
(2R,3S)-2-octadecylhexadecane-1,3-diol, 9a
d
203.6, 138.1, 137.6, 128.4, 128.5, 128.1, 127.7, 127.5, 84.0, 73.0, 72.8,
69.0, 41.7, 31.8, 29.6, 29.4, 29.0, 27.6, 26.8, 22.7, 14.1; IR (KBr): 3030,
2924, 2853, 1731, 1459, 1096, 738 cmꢀ1; MS (LC): m/z 559 [MþNa]þ;
ESI-HRMS: m/z calcd for C36H56O3Na [MþNa]þ 559.4127; found
559.4153.
Palladium (10%) on carbon (0.1 g) was added to the compound
8a (1.5 g, 2.18 mmol) dissolved in 30 mL EtOAc/MeOH (4:6), and the
mixture was stirred under the balloon pressure of H2 for 12 h. The
catalyst was filtered off, and washed with ethyl acetate (3ꢂ5 mL).
The combined organic layers were dried and concentrated under
reduced pressure. The residue was purified by column chroma-
4.9. (2S,3S)-2-(Benzyloxy)-3-((benzyloxy)methyl)heni-
cosanal, 7b
tography to give the corresponding 1,3-diol 9a (0.99 g, 92% yield) as
25
The compound 7b (2.8 g, 86% yield) as a colorless liquid was
synthesized from 6b (4 g, 6.57 mmol) according to typical pro-
a white solid. Mp 59–61 ꢁC; TLC, Rf 0.53 (30% EtOAc/hexane); [
a]
D
ꢀ5.0 (c 0.004, CHCl3); 1H NMR (200 MHz, CDCl3):
d 3.92–3.86 (m,
25
cedure 7a. TLC, Rf 0.50 (10% EtOAc/hexane); [
a
]
D
ꢀ7.8 (c 0.038,
1H), 3.71–3.55 (m, 2H), 2.5 (br s, 2H), 1.64–1.20 (m, 59H), 0.89 (t,
CHCl3); 1H NMR (200 MHz, CDCl3):
d
9.7 (d, J¼1.8 Hz, 1H), 7.31–7.27
J¼6.2 Hz, 6H); 13C NMR (75 MHz):
d 70.4, 63.9, 39.4, 33.2, 31.9, 29.8,
(m, 10H), 4.79 (d, J¼12.4 Hz, 1H), 4.48 (d, J¼12.4 Hz, 1H), 4.42 (s,
2H), 3.74–3.71 (m, 1H), 3.60–3.51 (m, 1H), 3.42–3.33 (m, 1H), 2.24–
2.17 (m, 1H), 1.34–1.20 (m, 34H), 0.89 (t, J¼6.5 Hz, 3H); 13C NMR
29.5, 28.5, 27.3, 24.5, 22.6, 14.1; IR (KBr): 3335, 2917, 2849, 1461,
1029, 718 cmꢀ1; MS (LC): m/z 533 [MþNa]þ; ESI-HRMS: m/z calcd
for C34H70O2Na [MþNa]þ 533.5273; found 533.5290.
(75 MHz): d 204.4, 138.2, 137.5, 128.4, 128.3, 128.0, 127.9, 127.5, 83.4,
73.0, 72.9, 69.3, 42.7, 31.9, 29.7, 29.6, 29.4, 29.3, 27.8, 27.3, 22.7, 14.1;
IR (KBr): 3021, 2927, 2853, 1732, 1495, 1376, 1209, 697 cmꢀ1; MS
(LC): m/z 559 [MþNa]þ.
4.13. (2R,3S)-2-Octadecylhexadecane-1,3-diol, 9b
The compound 9b (0.95 g, 88% yield) as a white solid, mp 58–
60 ꢁC, was synthesized from 8b (1.5 g, 2.18 mmol) according to
25
4.10. Typical procedure for the Wittig reaction: 1-(((R)-2-((S,
E/Z)-1-(benzyloxy)tetradec-2-enyl)icosyloxy)methyl)-
benzene, 8a
typical procedure 9a. TLC, Rf 0.53 (30% EtOAc/hexane); [
a]
þ2.6 (c
D
0.0075, CHCl3); 1H NMR (300 MHz, CDCl3):
d
3.93–3.89 (m, 1H),
3.65–3.61 (m, 2H), 1.59–1.55 (m, 1H), 1.40–1.25 (m, 58H), 0.89 (t,
J¼6.2 Hz, 6H); 13C NMR (75 MHz):
d 70.5, 63.9, 39.3, 33.2, 31.9, 31.7,
29.8, 29.5, 28.6, 27.3, 24.4, 22.5, 14.1; IR (KBr): 3452, 2927, 2820,
To a solution of n-dodecyl-triphenylphosphonium bromide
(3.81 g, 7.46 mmol) in anhydrous THF (10 mL) at ꢀ18 ꢁC was added
1252, 1034, 778 cmꢀ1; MS (LC): m/z 533 [MþNa]þ.

G. Kumaraswamy, B. Markondaiah / Tetrahedron 64 (2008) 5861–5865
5865
4.14. Typical procedure for the oxidation reaction: (S)-2-((S)-
4.17. (3R,4R)-3-Octadecyl-4-tridecyloxetan-2-one, 1b
1-hydroxytetradecyl)icosanoic acid, 10a
The compound 1b (0.106 g, 72% yield) as a white solid, mp 63–
To a stirred solution of the 1,3-diol 9a (0.50 g, 0.98 mmol) in
CH2Cl2 (20 mL) was added TEMPO (0.05 mg, 0.29 mmol) followed
by iodobenzene diacetate (0.95 g, 2.94 mmol). After 2 h, the re-
action mixture was treated with 5% aqueous Na2S2O3 (10 mL) and
saturated aqueous NaHCO3 (10 mL). After 15 min, the organic phase
was separated and the aqueous phase extracted with Et2O. The
combined organic extracts were dried and concentrated under re-
duced pressure. The crude product was purified by column chro-
matography to give the respective aldehyde, which was subjected
to further oxidation.
64 ꢁC, was synthesized from 10b (0.15 g, 0.29 mmol) according to
25
typical procedure 1a. TLC, Rf 0.71 (10% EtOAc/hexane); [
a
]
þ13.5 (c
D
0.01, CHCl3); 1H NMR (200 MHz, CDCl3):
d
4.19 (ddd, J¼7.2, 6.2,
3.9 Hz, 1H), 3.15 (ddd, J¼8.5, 6.6, 3.9 Hz, 1H), 1.84–1.62 (m, 4H),
1.41–1.20 (m, 54H), 0.88 (t, J¼6.4 Hz, 6H); 13C NMR (75 MHz):
d
171.6, 78.1, 56.1, 34.4, 31.9, 29.7, 29.2, 27.8, 25.0, 22.6, 14.0; IR
(KBr): 2927, 2852, 1810, 1449, 1381, 1143, 833, 759 cmꢀ1; MS (LC):
m/z 507 [MþH]þ; ESI-HRMS: m/z calcd for C34H66O2Na [MþNa]þ
529.4960; found 529.4957.
The above b-hydroxy aldehyde was dissolved in t-BuOH (10 mL)
Acknowledgements
and treated with a freshly prepared solution of NaClO2 (0.88 g,
9.70 mmol) in 20% aq NaH2PO4 (10 mL) at 0 ꢁC. After 4 h of vigorous
stirring at 0 ꢁC to rt, the reaction mixture was poured into EtOAc
(30 mL) and the aq layer was extracted with EtOAc (4ꢂ10 mL). The
combined organic layers were concentrated under reduced pres-
sure. The residue was purified by column chromatography to give
We are grateful to Dr. J. S. Yadav, Director, IICT, for his constant
encouragement. The DST, New Delhi (Grant No: SR/SI/OC-12/2007)
is also gratefully acknowledged for its financial assistance. Thanks
are also due to Dr. T. K. Chakraborty for his support. B.M. is thankful
to UGC (New Delhi) for awarding the fellowship.
the
b-hydroxy acid 10a (0.39 g, 85% yield) as a white solid. Mp 62–
25
64 ꢁC; TLC, Rf 0.31 (30% EtOAc/hexane); [
a
]
ꢀ4.2 (c 0.001, CHCl3);
D
Supplementary data
1H NMR (300 MHz, CDCl3):
d 3.70–3.63 (m, 1H), 2.45–2.33 (m, 1H),
1.76–1.58 (m, 1H), 1.38–1.20 (m, 57H), 0.89 (t, J¼6.8 Hz, 6H); 13C
Copies of spectra of 4a, 5a, 1a, 4b, 5b, and 1b can be found in the
Supplementary data. Supplementary data associated with this ar-
ticle can be found in the online version, at doi:10.1016/
j.tet.2008.04.062.
NMR (75 MHz):
d 177.0, 70.7, 51.7, 33.2, 32.0, 31.5, 29.8, 29.6, 29.3,
29.2, 24.4, 22.5, 14.1; IR (KBr): 3421, 2920, 2851, 1721, 1463, 1214,
849 cmꢀ1; MS (LC): m/z 547 [MþNa]þ; ESI-HRMS: m/z calcd for
C
34H68O3Na [MþNa]þ 547.5066; found 547.5092.
References and notes
1. (a) Umezawa, H.; Aoyagi, T.; Uotani, K.; Hamada, M.; Takeuchi, T.; Takahashi, S. J.
Antibiot. 1980, 33, 1594; (b) Uotani, K.; Naganawa, H.; Kondo, S.; Aoyagi, T.;
Umezawa, H. J. Antibiot. 1982, 35, 1495; (c) Weibel, E. K.; Hadvary, P.; Hochuli, E.;
Kupfer, E.; Lengsfeld, H. J. Antibiot. 1987, 40, 1081; (d) Hochuli, E.; Kupfer, E.;
Maurer, R.; Meister, W.; Mercadal, Y.; Schmidt, K. J. Antibiot. 1987, 40, 1086; (e)
Mutoh, M.; Nakada, N.; Matsukuma, S.; Ohshima, S.; Yoshinari, K.; Watanabe, J.;
Arisawa, M. J. Antibiot. 1994, 47, 1369; (f) Asai, A.; Hasegawa, A.; Ochiai, K.;
Yamashita, Y.; Mizukami, T. J. Antibiot. 2000, 53, 81; (g) Aldridge, D. C.; Gile, D.;
Turner, W. B. J. Chem. Soc. C 1971, 3888; (h) Pommier, A.; Pons, J.-M.; Kocienski,
P. J. J. Org. Chem. 1995, 60, 7334; (i) Pommier, A.; Pons, J.-M.; Kocienski, P. J.;
Wong, L. Synthesis 1994, 1294.
2. Lall, M. S.; Ramtohul, Y. K.; James, M. N. G.; Vederas, J. C. J. Org. Chem. 2002, 67,
1536.
3. (a) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H.
W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255 and references cited
therein; (b) Tomoda, H.; Ohbayashi, N.; Kumagai, H.; Hashizume, H.; Sunazuka,
T.; Omura, S. Biochem. Biophys. Res. Commun. 1999, 265, 536.
4.15. (R)-2-((R)-1-Hydroxytetradecyl)icosanoic acid, 10b
The compound 10b (0.37 g, 82% yield) as a white solid, mp 61–
63 ꢁC, was synthesized from 9b (0.50 g, 0.98 mmol) according to
25
typical procedure 10a. TLC, Rf 0.31 (30% EtOAc/hexane); [
a
]
D
þ2.3
(c 0.006, CHCl3); 1H NMR (200 MHz, CDCl3):
d
3.68–3.55 (m, 1H),
2.48–2.30 (m, 1H), 1.74–1.57 (m, 1H), 1.35–1.21 (m, 57H), 0.89 (t,
J¼6.8 Hz, 6H); 13C NMR (75 MHz):
d 177.0, 70.6, 51.7, 33.1, 31.9, 31.5,
29.8, 29.6, 29.3, 29.2, 27.2, 22.5, 14.1; IR (KBr): 3454, 3027, 2922,
1709, 1247, 993, 747 cmꢀ1; MS (LC): m/z 547 [MþNa]þ.
4. (a) Tomoda, H.; Omura, S. Yakugaku Zasshi-J. Pharm. Soc. Jpn. 2000, 120, 935; (b)
Masse, C. E.; Morgan, A. J.; Adams, J.; Panek, J. S. Eur. J. Org. Chem. 2000, 14, 2513.
5. Mikami, Y.; Yazawa, Y.; Tanaka, Y.; Ritzau, M.; Grafe, U. Nat. Prod. Lett. 1999, 13,
277.
4.16. Typical procedure for the
3-octadecyl-4-tridecyloxetan-2-one, 1a
b-lactone formation: (3S,4S)-
6. Sun, Y.-P.; Wu, Y. Synlett 2005, 1477.
7. (a) Calter, M. A.; Tretyak, O. A.; Flaschenriem, C. Org. Lett. 2005, 7, 1809; (b) Zhu,
C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126, 5352; (c) Wedler, C.;
Kunath, A.; Schick, H. J. Org. Chem. 1995, 60, 758; (d) Wedler, C.; Kleiner, K.;
Kunath, A.; Schick, H. Liebigs Ann. 1996, 881.
8. Purohit, V. C.; Richardson, R. D.; Smith, J. W.; Romo, D. J. Org. Chem. 2006, 71,
4549.
9. (a) Kumaraswamy, G.; Padmaja, M.; Markondaiah, B.; Jena, N.; Sridhar, B.;
Udaykiran, M. J. Org. Chem. 2006, 71, 337; (b) Kumaraswamy, G.; Markondaiah,
B. Tetrahedron Lett. 2007, 48, 1707; (c) Kumaraswamy, G.; Markondaiah, B.
Tetrahedron Lett. 2008, 49, 327; (d) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc.
Chem. Res. 2004, 37, 580; (e) List, B. Tetrahedron 2002, 58, 5573.
10. The anti/syn diastereomers were separated through silica gel column chro-
matography eluting with hexane/EtOAc as solvent. The enantioselectivity and
A solution of b-hydroxy acid 10a (0.15 g, 0.29 mmol) in CH2Cl2
(10 mL) was treated with Et3N (0.122 mL, 0.875 mmol) and BOPCl
(0.11 g, 0.44 mmol) at 23 ꢁC. After 1 h, the resulting reaction mix-
ture was diluted with water (1ꢂ0.5 mL) and extracted with EtOAc
(3ꢂ15 mL). The combined organic phases were dried and concen-
trated under reduced pressure. The crude residue was purified by
column chromatography to give the title compound 1a (0.106 g,
72% yield) as a white solid. Mp 65–66 ꢁC (lit.5 66–68 ꢁC); TLC, Rf
0.71(10% EtOAc/hexane); [
(200 MHz, CDCl3):
a
]
D
ꢀ12.66 (c 0.01, CHCl3); 1H NMR
25
d
4.17 (ddd, J¼7.4, 6.0, 3.8 Hz, 1H), 3.13 (ddd,
absolute configuration of the major compound 4a were determined on the
J¼8.7, 6.4, 3.8 Hz, 1H), 1.9–1.6 (m, 4H), 1.40–1.18 (m, 54H), 0.88 (t,
25
basis of [
a
]
value of the final product 1a.
D
J¼6.8 Hz, 6H); 13C NMR (75 MHz):
d 171.6, 78.1, 56.1, 34.4, 31.9, 29.7,
11. (a) Enders, D.; Grondal, C. Angew. Chem., Int. Ed. 2005, 44, 1210; (b) Bahmanyar,
S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475; (c) Hoang,
L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16; (d) Bah-
manyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 12911.
12. (a) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974; (b) Vatele, J.-M. Tetrahedron Lett. 2006, 47, 715.
29.6, 29.4, 29.3, 29.2, 27.9, 27.0, 25.0, 22.7, 14.1; IR (KBr): 2918, 2851,
1803, 1471, 1143, 863, 716 cmꢀ1; MS (LC): m/z 507 [MþH]þ; ESI-
HRMS: m/z calcd for C34H66O2Na [MþNa]þ 529.4960; found
529.4962.