First stereoselective total synthesis of decarestrictine O via RCM protocol

Article abstract of DOI:10.1016/j.tetlet.2010.05.064

A convergent first stereoselective total synthesis of decarestrictine O via RCM protocol starting from 1,3-propanediol and propylene oxide is reported.

Full text of DOI:10.1016/j.tetlet.2010.05.064

Tetrahedron Letters 51 (2010) 4017–4019
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First stereoselective total synthesis of decarestrictine O via RCM protocol
*
Palakodety Radha Krishna , T. Jagannadha Rao
D-211, Discovery Laboratory, Organic Chemistry Division-III, 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 convergent first stereoselective total synthesis of decarestrictine O via RCM protocol starting from 1,3-
propanediol and propylene oxide is reported.
Received 31 March 2010
Revised 12 May 2010
Accepted 17 May 2010
Available online 31 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Decarestrictine O
Propylene oxide
Jacobsen hydrolytic kinetic resolution
Sharpless asymmetric epoxidation
Yamaguchi esterification
Grubbs’ II generation catalyst
Decarestrictines represent a family of novel 10-membered lac-
tones produced by different strains of Penicillium.1 So far, six com-
ponents of the family of decarestrictines have been identified. The
identical carbon skeleton that constitutes a 10-membered lactone
ring varies in the oxygen patterns ranging from carbon 3–7 and
the presence of one E-configured double bond located either at
C-4 or at C-5. This seems to be a result of dehydration during bio-
synthesis. The decarestrictines show interesting activity in cell line
tests with HEP-G2 liver cells2,3 due to an inhibitory effect on cho-
lesterol biosynthesis. Against this backdrop, we embarked on a
program to synthesize some members of this class of compounds.
Earlier, we accomplished the total synthesis of the most potent
member of this family, decarestrictine D4a and other bio-active
10-membered macrolides as well.4b,4c Later we took up the synthe-
sis of decarestrictine O for two reasons. The first one being, to the
best of our knowledge, so far no synthesis has been reported for 1
and the other one is to accomplish a total synthesis involving RCM
(of 2, Scheme 1) as the key reaction. Though 10-membered macro-
lides were earlier synthesized via RCM,5 their synthesis through
RCM is still a challenging proposition because such a strategy is
highly dependent on substrate as well as on its compatible protect-
ing groups at allylic positions besides the low predictability of the
olefin geometry. Herein we report the first stereoselective total
synthesis of decarestrictine O 1 by a convergent strategy wherein
both the advanced intermediates are derived from the inexpensive
starting materials viz. 1,3-propanediol and propylene oxide.
Our strategy relies on Jacobsen kinetic resolution, Sharpless
asymmetric epoxidation, Yamaguchi esterification, and ring-clos-
ing metathesis (RCM) as the key steps. Retrosynthetic analysis re-
veals that the target compound 1 (Scheme 1) can be obtained from
RCM of diene 2 and subsequent deprotection of PMB-group, diene
2 in turn, could be obtained from Yamaguchi esterification of 4 and
3. Acid 3 can be realized from epoxy alcohol 6 which in turn could
be obtained starting from 1,3-propanediol by simple chemical
transformations. And hydroxy alkene 4 can be realized from pro-
pylene oxide through simple chemical transformations.
Accordingly, the synthesis of 1 starts with known allylic alcohol
56 (Scheme 2) from propanediol that was subjected Sharpless
asymmetric epoxidation once with [(+)-DIPT/Ti(OiPr)4/cumenehy-
droperoxide/ꢀ20 °C] to afford epoxy alcohol 67 (75%) which was
converted to allylic alcohol 7 by a two step process; first by con-
verting to chloro epoxy compound which on Na/ether mediated-
elimination afforded the allylic alcohol 7 (75% yield over two
steps). The hydroxyl group in 7 was protected as its PMB ether
(PMB-Br/NaH/THF/0 °C to rt) to afford 8 (90%), and the TBDPS
group in 8 was deprotected with TBAF in THF to afford primary
alcohol 9 (91%) which were converted to acid 3 by a two-step
process firstly; to an aldehyde by Swern oxidation and then by
perchlorite oxidation (NaClO2/NaH2PO4ꢁ2H2O/t-BuOH/2-methyl-
2-butene) to afford acid 35a (80% over two steps).
Hydroxy alkene
4 (Scheme 3) was synthesized from the
known chiral propyleneoxide8 and its ring-opening reaction with
THP-protected propargyl alcohol followed by protection–deprotec-
tion-LAH reduction gave the allylic alcohol 10 in good yields.
Allylic alcohol 10 on benzoylation under conventional conditions
* Corresponding author. Tel.: +91 40 27193158; fax: +91 40 27160387.
E-mail address: prkgenius@iict.res.in (P.R. Krishna).
followed by Sharpless dihydroxylation (AD-mix-a) and protection
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.064

4018
P. R. Krishna, T. J. Rao / Tetrahedron Letters 51 (2010) 4017–4019
O
OPMB
O
O
OPMB
1,3-Propanediol
O
HO
O
3
O
HO
OH
O
OH
O
2
1
OH
O
4
O
Scheme 1. Retrosynthetic analysis.
OH
O
a
b
TBDPSO
TBDPSO
OH
TBDPSO
OH
7
5
6
O
OPMB
OPMB
OPMB
e
d
c
HO
HO
TBDPSO
3
9
8
Scheme 2. Synthesis of acid 3. Reagents and conditions: (a) (+)-DIPT, Ti(OiPr)4, cumenehydroperoxide, CH2Cl2, ꢀ20 °C, 12 h, 75%; (b) (i) CCl4, Ph3P, NaHCO3, reflux, 1 h, (ii) Na/
ether, ether, 0 °C to rt, 3 h (75% over two steps); (c) PMB-Br, NaH, THF, 0 °C to rt, 12 h, 90%; (d) TBAF, THF, 0 °C to rt, 2 h, 91%; (e) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 1 h;
(ii) NaClO2, NaH2PO4ꢁ2H2O, t-BuOH/2-methyl-2-butene (3:1), 0 °C to rt, 12 h, 80% for two steps).
OPMB
PMBO
O
PMBO
O
O
a
c
b
OH
OH
OBZ
10
12
11
O
O
PMBO
O
OH
O
d
e
4
13
O
O
Scheme 3. Synthesis of alcohol 4. Reagents and conditions: (a) Ref. 8; (b) (i) Bz–Cl, Et3N, 0 °C to rt, (ii) AD-mix-ß, 75%, (iii) 2,2-DMP, CH2Cl2, PTSA; (c) K2CO3, MeOH, 2 h (75%
over three steps); (d) (i)(COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 1 h, (ii) Ph3PCH3þIꢀ, KOt-Bu, THF, 0 °C, 8 h, 78% (over two steps); (e) DDQ, CH2Cl2/H2O (19:1), rt, 1 h, 93%.
O
O
OPMB
O
a
c
b
O
O
O
3
4
+
HO
OH
OPMB
O
O
2
OH
1
O
O
14
Scheme 4. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 0 °C to rt, 4 h, then DMAP, 4, toluene, 0 °C to rt, 12 h, 88%; (b) Grubbs’ II generation catalyst
(10 mol %), CH2Cl2, reflux, 12 h, 75%; (c) TFA, CH2Cl2, rt, 1 h, 68%.
of the ensuing diol as acetonide afforded compound 11 (75% over
three steps). Compound 11 on debenzoylation, Swern oxidation
followed by 1C Wittig olefination (Ph3PCH3þIꢀ/KOt-Bu/THF) affor-
ded epoxy alkene 13 (78% over two steps). The PMB-group in 13
was deprotected with DDQ in CH2Cl2/H2O to obtain intermediate
4 (93%).
With two building blocks 3 and 4 in hand, the next task was to
couple them as ester (Scheme 4) under Yamaguchi esterification
protocol9 (2,4,6-trichloro benzoyl chloride/Et3N/THF then DMAP/
toluene) to afford the diene 2 (88%). The diene 2 underwent RCM
smoothly using Grubb’s II generation catalyst to yield lactone10
14 (75%) as a chromatographically separable mixture in 80:20 ratio
in favor of E-isomer. The compound was characterized by its spec-
tral data.11 The geometry of the olefin was established as ‘E’ from
its coupling constants, while one of the olefinic proton appeared
at d 5.75 ppm as a double doublet (J = 8.3, 15.6 Hz) and the other
one showed at d 5.57 ppm as a double doublet (J = 9.3, 15.6 Hz). Fi-
nally lactone 14 on global deprotection of PMB ether and acetonide

P. R. Krishna, T. J. Rao / Tetrahedron Letters 51 (2010) 4017–4019
4019
–OCH), 3.56–3.53 (m, 1H, –OCH), 1.96–1.87 (m, 1H, CH2), 1.71–1.63 (m, 1H,
CH2), 1.36 (d, J = 3.7 Hz, 6H, CH3), 1.25 (d, J = 6.1 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3): 135.5, 135.3, 135.1, 129.3, 129.1, 118.8, 114.2, 113.6, 108.4,
82.9, 77.4, 71.9, 69.0, 55.1, 38.3, 27.2, 26.8, 19.6; ESI-MS: m/z 333 [M+Na]+.
Anal. Calcd for C17H26O5: C, 65.78; H, 8.44. Found: C, 65.80; H, 8.50. Compound
(TFA/CH2Cl2/rt/1 h) afforded the final product decarestrictine O (1,
68%). The spectral data of the synthetic compound matched with
the literature values.3,11
In summary, we accomplished the first total synthesis of deca-
restrictine O via the RCM protocol.
13: yellow liquid; ½a D25
ꢂ
ꢀ4.4 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.18
(d, J = 9.0 Hz, 2H, Ar-H), 6.79 (d, J = 8.3 Hz, 2H, Ar-H), 5.79–5.68 (m, 1H,
olefinic), 5.35–5.28 (m, 1H, olefinic), 5.17 (d, J = 10.5 Hz, 1H, olefinic), 4.45 (d,
J = 11.3 Hz, 1H, –OCH2Ph), 4.35 (d, J = 11.3 Hz, 1H, –OCH2Ph), 3.98 (t, J = 7.5 Hz,
1H, –OCH), 3.78 (s, 3H, –OCH3), 3.74–3.66 (m, 2H, –OCH), 1.93–1.84 (m, 1H, –
CH2), 1.66–1.58 (m, 1H, –CH2), 1.36 (d, J = 3.7 Hz, 6H, –CH3), 1.19 (d, J = 6.1 Hz,
3H, –CH3); 13C NMR (75 MHz, CDCl3): 159.1, 135.2, 129.2, 119.1, 113.5, 108.5,
82.9, 77.4, 71.7, 69.7, 55.1, 38.5, 27.3, 19.9; IR (neat); 3049, 2932, 1614, 1512,
Acknowledgment
One of the authors (T.J.R.) thanks CSIR, New Delhi, for the finan-
cial support in the form of a fellowship.
1454, 1375, 1090, 824 cmꢀ1
;
ESI-MS: m/z 329 [M+Na]+. Anal. Calcd for
C
18H26O4: C, 70.56; H, 8.55. Found: C, 70.60; H, 8.52. Compound 4: yellow
References and notes
syrup oil; ½a 2D5
ꢂ
ꢀ15.5 (c 0.3, CHCl3): 1H NMR (500 MHz, CDCl3): d 5.78–5.71 (m,
1H), 5.35 (d, J = 10.7 Hz, 1H), 3.97–3.93 (m, 2H, –OCH), 3.73 (td, J = 2.9, 10.7 Hz,
1H, –OCH), 2.83 (br s, 1H, –OH), 1.65 (d, J = 14.6 Hz, 1H), 1.59–1.52 (m, 1H,
CH2), 1.40 (s, 6H, CH3), 1.16 (d, J = 5.8 Hz, CH3); 13C NMR (75 MHz, CDCl3): d
134.9, 119.4, 83.1, 80.9, 67.2, 40.1, 27.1, 26.9, 23.2; ESI-MS: m/z 209 [M+Na]+.
1. (a) Grabley, S.; Granzer, E.; Hütter, K.; Ludwig, D.; Mayer, M.; Thiericke, R.; Till,
G.; Wink, J.; Philipps, S.; Zeeck, A. J. Antibiot. 1992, 45, 56–65; (b) Göhrt, A.;
Zeeck, A.; Hütter, K.; Kirsch, R.; Kluge, H.; Thiericke, R. J. Antibiot. 1992, 45, 66–
73; (c) Ayer, W. A.; Sun, M.; Browne, L. M.; Brinen, L. S.; Clardy, J. J. Nat. Prod.
1992, 55, 649–653.
Compound 3: colorless liquid; ½a D25
ꢂ
ꢀ36.3 (c 0.50, CHCl3); 1H NMR (CDCl3,
300 MHz): d 7.16 (d, 2H, J = 8.3 Hz, Ar-H), 6.78 (d, 2H, J = 8.3 Hz, Ar-H), 5.82–
5.71 (m, 1H, olefinic), 5.34–5.23 (m, 2H, olefinic), 4.49 (d, 1H, J = 11.3 Hz,
–OCH2C6H4), 4.28 (d, 1H, J = 11.3 Hz, –OCH2C6H4), 4.25–4.16 (m, 2H, –OCH2),
3.78 (s, 3H, –OCH3), 2.64 (dd, 1H, J = 8.3, 15.8 Hz, –CH2), 2.51 (dd, 1H, J = 8.3,
15.8 Hz, 1H, –CH2). 13C NMR (75 MHz, CDCl3): d 159.1, 138.4, 129.3, 117.0,
113.6, 72.8, 70.7, 66.5, 55.5, 37.3, 25.9, 19.0; IR (neat): 3410, 2923, 2362, 1713,
1612, 1513 cmꢀ1; MS (ESI): 259 (M+Na)+ HRMS (C13H16O4Na) found: 259.0949
2. Javitt, N. B.; Budai, K. Biochem. J. 1989, 262, 989–992.
3. Mayer, M.; Thiericke, R. J. Antibiot. 1993, 46, 1372–1380.
4. (a) Radha Krishna, P.; Narasimha Reddy, P. V. Tetrahedron Lett. 2006, 47, 7473–
7476; (b) Radha Krishna, P.; Narsingam, M. Synthesis 2007, 3627–3634; (c)
Radha Krishna, P.; Sreeshailam, A. Synlett 2008, 2795–2798.
5. (a) Mohapatra, D. K.; Ramesh, D. K.; Giardello, M. A.; Chorghade, M. S.; Gurjar,
M. K.; Grubbs, R. H. Tetrahedron Lett. 2007, 48, 2621–2625; (b) Ramana, C. V.;
Khaladkar, T. P.; Chatterjee, S.; Gurjar, M. K. J. Org. Chem. 2008, 73, 3817–3822;
(c) Mohapatra, D. K.; Uttam, D.; Naidu, P. R.; Yadav, J. S. Synlett 2009, 2129–
2132.
calcd: 259.0940. Compound 2: yellow syrup; ½a D25
ꢂ
ꢀ12.8 (c 0.35, CHCl3); 1H
NMR (500 MHz, CDCl3): d 7.16 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 8.3 Hz, 2H), 5.78–
5.68 (m, 2H, olefinic), 5.33–5.17 (m, 4H, olefinic), 5.05 (q, J = 6.2 Hz, 1H, –OCH),
4.46 (d, J = 11.4 Hz, 1H, –OCH2Ph), 4.30 (d, J = 11.4 Hz,1H, –OCH2Ph), 4.19 (q,
J = 7.2 Hz, 1H, –OCH), 3.92 (t, J = 7.2 Hz, 1H, –OCH), 3.77 (s, 3H, CH3), 3.65 (hex,
J = 4.1 Hz,1H, –OCH), 2.56 (dd, J = 8.3, 14.5 Hz, 1H, CH2), 2.41 (dd, J = 6.2,
15.6 Hz, 1H, CH2), 1.85 (quin, J = 6.2 Hz, 1H, CH2), 1.72–1.65 (m, 1H, CH2), 1.34
(d, J = 15.6 Hz, 6H, CH3), 1.22 (d, J = 6.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d 170.1, 137.3, 135.1, 134.7, 129.5, 129.3, 119.4, 118.1, 117.8, 113.8, 82.6, 77.4,
76.3, 70.6, 68.5, 54.8, 41.3, 37.8, 27.3, 20.0, 19.6; HRMS m/z [M+Na]+ found
6. Allylic alcohol 5 was prepared by the synthetic route as shown below:
Imidazole,TBDPS-Cl
HO
OH
CH2Cl2, 0ºC-r.t
OTBDPS
HO
1.Swernoxidation
427.2091 calcd 427.2096 for C23H32O6Na. Compound 14: thick syrup: ½a D25
ꢂ
5
ꢀ52.2 (c 0.20, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.2 (d, J = 8.3 Hz, 2H, Ar-H),
6.82 (d, J = 8.3 Hz, 2H, Ar-H), 5.75 (dd, J = 8.3, 15.6 Hz, 1H, olefinic), 5.57 (dd,
J = 9.3, 15.6 Hz, 1H, olefinic), 5.10 (m, 1H, –OCH), 4.53 (d, J = 12.4 Hz, 1H,
OCH2Ph), 4.33–4.23 (m, 2H, –OCH), 3.93–3.83 (m, 4H, –OCH), 3.79 (s, 3H, CH3)
3.72 (t, J = 8.3 Hz, 1H, –OCH), 2.82 (dd, J = 9.3, 12.4 Hz, 1H, CH2), 2.51 (dd,
J = 3.1, 13.5 Hz, 1H, CH2), 2.33–2.25 (m, 1H, CH2), 1.75 (d, J = 15.6 Hz, 1H, CH2),
1.4 (d, J = 9.3 Hz, 6H, CH3), 1.28 (d, J = 6.2 Hz, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d 169.9, 134.3, 133.6, 131.3, 130.9, 129.1, 114.0, 113.6, 109.2, 84.1,
74.5, 70.6,68.4, 55.4, 43.2, 33.2, 29.6, 27.1, 18.7; HRMS m/z [M+Na]+ found
2 .PPh3 =CHCOOMe, CH2Cl2
3 .LAH/AlCl3, dry.ether, 0ºC-r.t
7. Sharpless, K. B.; Kolb, H. C.; VanNieuwenhze, M. S. Chem. Rev. 1994, 94, 2483–
2547.
8. Sharma, G. V. M.; Babu, K. V. Tetrahedron: Asymmetry 2007, 18, 2175–2184.
9. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
399.1772 calculated 399.1783 for C21H28O7Na. Compound 1: thick syrup; ½a D25
ꢂ
10. (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452; (b)
Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238; (c) Rawat, V.;
Chouthaiuuale, P. V.; Suryavanshi, G.; Sudalai, A. Tetrahedron: Asymmetry 2009,
20, 2173–2177; (d) Riatto, V. B.; Pilli, R. A.; Victor, M. M. Tetrahedron 2008, 64,
2279–2300; (e) Yadav, J. S.; Laxmi, K. A.; Mallikarjuna Reddy, N.; Prasad, A. R.;
Subbareddy, B. V. Tetrahedron 2010, 66, 334–338.
ꢀ18.5 (c 0.20, CH3OH); 1H NMR (500 MHz, acetone-d6): d 5.55 (dd, J = 7.1,
16.3 Hz, 1H, olefinic), 5.39 (dd, J = 8.1, 16.1 Hz, 1H, olefinic), 5.01 (m, 1H, -OCH),
4.57 (br s, 1H, –OH), 4.45 (m, 1H, –OCH), 4.26 (m, 1H, –OCH), 4.03 (br s, 1H,
–OH), 3.45–3.40 (m, 1H, –OCH), 2.89 (dd, J = 7.9, 13.3 Hz, 1H, –CH2), 2.31–2.25
(m, J = 4.5, 13.5 Hz, 1H, –CH2), 1.36 (dd, J = 3.2, 15.6 Hz, 1H, –CH2), 1.31 (m, 1H,
–CH2), 1.28 (d, J = 6.6 Hz, 3H, CH3); 13C NMR (100 MHz, acetone-d6): d 170.7,
135.7, 131.0, 76.9, 74.0, 73.2, 71.5, 45.2, 39.7, 21.2; IR (neat): 3399, 2924, 1717,
1459 cmꢀ1 HRMS m/z [M+Na]+ found 239.0889; calcd 239.0895 for
11. Spectral data for selected compounds. Compound 12: yellow liquid; ½a D25
ꢀ54.7 (c
ꢂ
0.20, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.18 (d, J = 8.3 Hz, 2H, Ar-H), 6.82 (d,
J = 8.3 Hz, 2H, Ar-H), 4.46 (d, J = 11.3 Hz, 2H, –OCH2Ph), 3.99–3.91 (m, 1H,
–OCH), 3.78 (s, 3H, OCH3), 3.74–3.67 (m, 1H, –OCH), 3.67 (d, J = 4.5 Hz, 1H,
C10H16O5Na.