Stereoselective total synthesis of (-)-decarestrictine D from l-malic acid

Article abstract of DOI:10.1016/j.tetlet.2006.08.035

A convergent stereoselective total synthesis of (-)-decarestrictine D from l-malic acid is reported.

Full text of DOI:10.1016/j.tetlet.2006.08.035

Tetrahedron Letters 47 (2006) 7473–7476
Stereoselective total synthesis of (ꢀ)-decarestrictine D
from L-malic acidI
Palakodety Radha Krishna* and P. V. Narasimha Reddy
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 13 July 2006; revised 4 August 2006; accepted 10 August 2006
Available online 1 September 2006
Abstract—A convergent stereoselective total synthesis of (ꢀ)-decarestrictine D from L-malic acid is reported.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
identified by many research groups worldwide as an
attractive synthetic target towards developing new cho-
lesterol-lowering drugs. Consequently, the synthesis of 1
and its seco acid have been reported by various research
groups.2–5
(ꢀ)-Decarestrictine D (1) was independently isolated
from different strains of Penicillium (P. corylophilum,
P. simplicissimum)1 and Polyporous tuberaster along
with various other 10-membered lactones (decarestric-
tines A1/A2, B, C1/C2) of this family. Among this class
of compounds, (ꢀ)-decarestrictine D potentially inhibits
liver cell cholesterol biosynthesis (HEP cells, IC50 of
100 nm)1 and the structural difference between 1 and
other inhibitors such as mevinolin and compactin
suggests a different mode of action. Also, 1 is highly
bio-selective with no significant antibacterial, anti-
fungal, antiprotozoal or antiviral activity.1 Considering
its selective biological profile, compound 1 has been
As part of our interest in the synthesis of bioactive nat-
ural products,6 herein, we report a stereoselective total
synthesis of (ꢀ)-decarestrictine D by a convergent strat-
egy wherein both the intermediates are derived from the
common, inexpensive starting material, L-malic acid.
Our strategy relies on Sharpless asymmetric epoxida-
tion, acetylenic addition onto a chiral aldehyde, 1,
2-syn selective reduction and Yamaguchi macrolacton-
ization as the key steps. Retrosynthetic analysis reveals
Retrosynthetic analysis
O
OH OBn
OBn
COOH
O
OBn
2
HO
OH
1
OH
OBn
PMBO
OBn
OHC
OTBDPS
4
OBn
L-Malic acid
PMBO
OBn
OTBDPS
3
OH
5
Keywords: Decarestrictine D; L-Malic acid; 1,2-syn selective reduction; Sharpless asymmetric epoxidation; Yamaguchi macrolactonization.
q IICT Communication No. 060707.
*
Corresponding author. Tel.: +91 40 27160123; fax: +91 40 27160387; e-mail: prkgenius@iict.res.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.035

7474
P. Radha Krishna, P. V. Narasimha Reddy / Tetrahedron Letters 47 (2006) 7473–7476
OBn
OH
OBn
c
a
b
O
HO
HO
O
OHC
OTBDPS
OTBDPS
OTBDPS
OH
4
7
8
6
c, d
O
OH
O
f
O
g
e
O
i
O
O
O
COOEt
OH
10
11
9
OH
OBn
OBn
PMBO
h
OBn
HO
HO
13
5
12
Scheme 1. Reagents and conditions: (a) (i) TBDPSCl, imidazole, CH2Cl2, 0 ꢁC–rt, 4 h (90%); (ii) CSA, MeOH, rt, 0.5 h (85%); (b) (i) a,a-
Dimethoxytoluene, PPTS, CH2Cl2, 0 ꢁC–rt, 3 h (78%); (ii) DIBAL–H, CH2Cl2, 0 ꢁC–rt, 3 h (75%); (c) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC
(95%); (d) Ph3PCHCOOEt, benzene, reflux, 2 h (70%); (e) LiAlH4/AlCl3, ether, 0 ꢁC, 6 h (65%); (ii) (+)-DIPT, Ti(OiPr)4, cumene hydroperoxide,
CH2Cl2, ꢀ20 ꢁC, 12 h (85%); (f) CCl4, Ph3P, NaHCO3, reflux, 1 h (90%); (ii) LDA, THF, ꢀ78 ꢁC to ꢀ40 ꢁC, 3 h (65%); (g) (i) BnBr, NaH, THF,
0 ꢁC–rt, 6 h (80%); (ii) CSA, MeOH, rt, 0.5 h (85%); (h) (i) TsCl, Et3N, CH2Cl2, 0 ꢁC–rt, 12 h (75%); (ii) LiAlH4, THF, 0 ꢁC–rt, 2 h (90%); (i) PMBBr,
NaH, THF, 0 ꢁC–rt, 12 h (75%).
that target compound 1 can be obtained from seco acid
2 by Yamaguchi macrolactonization and subsequent
deprotection of the benzyl groups. Seco acid 2, in turn,
could be obtained from chiral propargylic alcohol 3 and
compound 3 itself by coupling fragments 4 and 5 fol-
lowed by an oxidation–reduction protocol to generate
the 1,2-syn diol system. Both fragments 4 and 5 can be
realized independently from L-malic acid by simple
chemical transformations.
the corresponding diol 12 (85%). The primary hydroxyl
group in diol 12 was selectively monotosylated (TsCl/
Et3N/CH2Cl2/rt), which upon exhaustive reduction
(excess LiAlH4/THF) generated alkyne 13 with the
terminal methyl group being installed. Finally, the sec-
ondary hydroxyl group was protected as its PMB ether
(PMBBr/NaH/THF/rt) to furnish fragment 5.
In order to prepare 3, alkyne 5 (Scheme 2) was treated
with n-BuLi in THF at ꢀ78 ꢁC and the resulting acetyl-
enic anion was quenched with 4 to yield 14 (70%) as a
diastereomeric mixture (de 20%). In order to increase
the diastereoslectivity, and to obtain the requisite stereo-
centre at the newly created site, hydroxy alkyne 14 was
oxidized to its corresponding keto compound (Dess–
Martin periodinane/CH2Cl2) and selectively reduced
with K-Selectride8 in THF at ꢀ78 ꢁC to give 3 (80%)
and its diastereomer (15%) (de 70%) as a separable mix-
ture. The reaction of 3 with Red-Al, in diethyl ether gave
the corresponding olefin, and the resulting allylic hydr-
oxyl group was protected as its benzyl ether (BnBr/
NaH/THF–DMF/rt) to afford 15 (75%). TBDPS depro-
tection (TBAF/THF/rt) afforded primary alcohol 16
(95%), which was oxidized to the corresponding acid
by a two-step process; firstly to an aldehyde by Swern
oxidation and then on perchlorite oxidation (NaClO2/
NaH2PO4.2H2O/t-BuOH/2-methyl-2-butene) to the acid
17 (80% over two steps). Treatment with DDQ in
CH2Cl2–H2O afforded seco acid 2 as its tri benzyl ether
derivative. Yamaguchi macrolactonization9 yielded 18
2. Results and discussion
Accordingly, the synthesis of 1 starts with compound 6
(Scheme 1), which is readily obtained from L-malic
acid.7 Thus, 6 was silylated (TBDPSCl/imidazole/
CH2Cl2/rt) and then on exposure to CSA in MeOH gave
diol 7 (85%). Diol 7 was converted into a benzylidene
derivative (a,a-dimethoxytoluene/PPTS/CH2Cl2), which
on subsequent regioselective reductive ring-opening
reaction with DIBAL–H in CH2Cl2 afforded the free
primary alcohol 8 (75%), which was oxidized under
Swern conditions to afford aldehyde 4 (95%).
To prepare alkyne 5, alcohol 6 was subjected to Swern
oxidation followed by a Wittig olefination reaction
(Ph3PCHCOOEt/benzene/reflux) to afford trans a,b-
unsaturated ester 9 (70%). The reduction with LiAlH4–
AlCl3 in diethyl ether and then exposure of the ensuing
allylic alcohol to Sharpless epoxidation [(+)-DIPT/
Ti(OiPr)4/cumene
hydroperoxide/CH2Cl2/ꢀ20 ꢁC]
(45%) and finally global debenzylation (TiCl4/CH2Cl2/
25
0 ꢁC–rt) gave the target compound 1 (65%), ½aꢁD ꢀ60:3
25
afforded epoxy alcohol 10 (85%). Epoxide 10 was chlo-
rinated (CCl4/Ph3P/reflux) followed by a base induced
double elimination (LDA/THF) to afford propargylic
alcohol 11. The hydroxyl group in 11 was protected as
its benzyl ether (BnBr/NaH//THF/rt) and the cyclo-
hexylidene group was cleaved (CSA/MeOH/rt) to afford
(c 0.4, CHCl3) {natural 1; ½aꢁD ꢀ62:0 (c 1.0, CHCl3)1a
25
25
and synthetic 1, [aꢁD ꢀ67:0 (c 0.26, CHCl3),2 ½aꢁD ꢀ68
(c 0.066, CHCl3)5}. The physical and spectroscopic data
of our synthetic sample 110 were identical to those of the
reported natural and synthetic products.

P. Radha Krishna, P. V. Narasimha Reddy / Tetrahedron Letters 47 (2006) 7473–7476
7475
PMBO
OBn
PMBO
OBn
3
OBn
OBn
a
b
5
OTBDPS
OTBDPS
OTBDPS
14
OH
OH
PMBO
OBn
OBn
PMBO
PMBO
OBn
OBn
d
c
OH
15
16
OBn
OBn
OBn
OH OBn
OBn
OBn
f
e
COOH
COOH
2
17
OBn
OBn
O
O
g
h
1
BnO
OBn
OBn
18
Scheme 2. Reagents and conditions: (a) n-BuLi, 4, THF, ꢀ78 ꢁC, 3 h (70%); (b) (i) Dess–Martin periodinane, CH2Cl2, 0 ꢁC–rt, 2 h (90%); (ii) K-
Selectride, THF, ꢀ78 ꢁC, 3 h (80%); (c) (i) Red-Al, ether, 0 ꢁC–rt, 2 h (95%); (ii) BnBr, NaH, THF–DMF (9:1), 0 ꢁC–rt, 4 h (75%); (d) TBAF, THF,
0 ꢁC–rt, 12 h (95%); (e) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC 1 h; (ii) NaClO2, NaH2PO4 Æ2H2O, t-BuOH–2-methyl-2-butene (3:1), 0ꢁC–rt, 12 h
(80% for two steps); (f) DDQ, CH2Cl2–H2O (19:1), rt, 1 h, (80%); (g) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 0 ꢁC–rt, 4 h, then DMAP, toluene,
reflux, 12 h (45%); (h) TiCl4, CH2Cl2, 0 ꢁC–rt, 1 h (65%).
Zeeck, A. J. Antibiot. 1992, 45, 56–65; (b) Go¨hrt, A.;
Zeeck, A.; Hutter, K.; Kirsch, R.; Kluge, H.; Thiericke, R.
¨
J. Antibiot. 1992, 45, 66–73; (c) Ayer, A. W.; Sun, M.;
Browne, L. M.; Brinen, L. S.; Clardy, J. J. Nat. Prod.
1992, 55, 649–653.
The present synthesis of 1 differs from that published by
Andrus et al.2 in the sense that 1,2-syn selective reduction
of the ketone of 14 derived from L-malic acid was in-
voked for accessing the vicinal syn diol system (15) in a
more defined manner. This overcomes the ambiguity
arising from isomeric products obtained during Sharp-
less dihydroxylation of a diene as in the earlier strategy.
Likewise, one of the hydroxyl groups (C9–OH) of the
1,3-anti diol system was realized from the pre-existing
chirality in L-malic acid and the other (C7–OH) through
the Sharpless asymmetric epoxidation protocol.
2. Andrus, M. B.; Shih, T.-L. J. Org. Chem. 1996, 61, 8780–
8785.
3. (a) Pilli, R. A.; Victor, M. M. Tetrahedron Lett. 1998, 39,
4421–4424; (b) Pilli, R. A.; Victor, M. M. J. Braz. Chem.
Soc. 2001, 12, 373–385.
4. Colle, S.; Taillefumier, C.; Chapleur, Y.; Liebl, R.;
Schmidt, A. Bioorg. Med. Chem. 1999, 7, 1049–1057.
5. Kobayashi, Y.; Asano, M.; Yoshida, S.; Takeuchi, A. Org.
Lett. 2005, 7, 1533–1536.
6. (a) Radha Krishna, P.; Narasimha Reddy, P. V. Tetra-
hedron Lett. 2006, 47, 4627–4630; (b) Radha Krishna, P.;
Ramana Reddy, V. V. Tetrahedron Lett. 2005, 46, 3905–
3907; (c) Radha Krishna, P.; Narsingam, M.; Kannan, V.
Tetrahedron Lett. 2004, 45, 4773–4775; (d) Radha
Krishna, P.; Ramana Reddy, V. V.; Sharma, G. V. M.
Synthesis 2004, 2107–2114.
3. Conclusion
In conclusion, a stereoselective synthesis of (ꢀ)-decare-
strictine D 1 was accomplished by means of a versatile
strategy, wherein L-malic acid was used as the common
starting material for accessing both the advanced inter-
mediates for use in a convergent total synthesis.
7. Hanessian, S.; Ugolini, A.; Dube, D.; Glamyan, A. Can. J.
Chem. 1984, 62, 2146–2147.
8. Takahashi, T.; Miyazawa, M.; Tsuji, J. Tetrahedron Lett.
1985, 26, 5139–5142.
Acknowledgement
9. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yama-
guchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
10. The spectral data of selected compounds. Compound 3:
One of the authors (P.V.N.R.) thanks the CSIR, New
Delhi, for financial support in the form of a fellowship.
25
Thick syrup; ½aꢁD ꢀ108:46 (c 2.0, CHCl3); 1H NMR
(200 MHz, CDCl3): d 7.61 (d, 4H, J = 7.2 Hz), 7.37–7.30
(m, 6H), 7.26–7.23 (m, 10H), 7.08 (d, 2H, J = 8.3 Hz), 6.73
(d, 2H, J = 8.3 Hz), 4.73–4.67 (m, 2H), 4.60 (d, 1H,
J = 11.3 Hz), 4.46–4.27 (m, 5H), 4.16 (d, 1H,
J = 11.1 Hz), 3.78–3.75 (m, 3H), 3.72 (s, 3H), 2.06–1.80
(m, 4H), 1.16 (d, 3H, J = 5.8 Hz), 1.04 (s, 9H); 13C NMR
References and notes
1. (a) Grabley, S.; Granzer, E.; Hutter, K.; Ludwig, D.;
¨
Mayer, M.; Thiericke, R.; Till, G.; Wink, J.; Philipps, S.;

7476
P. Radha Krishna, P. V. Narasimha Reddy / Tetrahedron Letters 47 (2006) 7473–7476
(75 MHz, CDCl3): 136.48, 129.63, 129.28, 128.35, 128.00,
127.65, 127.56, 113.66, 85.09, 84.51, 79.39, 73.37, 70.72,
70.46, 70.19, 65.34, 64.70, 60.22, 55.15, 43.84, 34.03, 29.64,
126.00, 79.52, 78.02, 73.39, 71.04, 70.26, 42.83, 36.92,
29.23, 20.03; IR (thin film) 2923, 2855, 1727, 1096,
1068 cmꢀ1; ESIMS; 487 (M+H)+, 509 (M+Na)+. Anal.
Calcd for C31H34O5: C, 76.52; H, 7.04. Found: C, 76.58;
H, 7.01%. Compound 1: Yellowish solid; mp = 115–
26.79, 19.66; IR (thin film) 3449, 2926, 1637, 1107 cmꢀ1
;
ESIMS; 779 (M+Na)+. Anal. Calcd for C48H56O6Si: C,
76.15; H, 7.46; Si, 3.71. Found: C, 76.19; H, 7.41; Si,
25
118 ꢁC; ½aꢁ ꢀ60:3 (c 0.4, CHCl3); 1H NMR (300 MHz,
25
3.67%. Compound 2: Thick syrup; ½aꢁD ꢀ57:52 (c 0.6,
CDCl3): d D5.90 (dd, 1H, J = 8.1, 11.6 Hz), 5.87 (dd, 1H,
J = 2.1, 15.8 Hz), 5.24 (ddq, 1H, J = 1.7, 6.4, 12.5 Hz),
4.41 (dd, 1H, J = 1.4, 3.7 Hz), 4.19 (ddd, 1H, J = 3.9, 8.4,
11.7 Hz), 4.09–4.00 (br s, 1H), 2.61 (dd, 1H, J = 1.7,
14.3 Hz), 2.39 (dd, 1H, J = 6.4, 14.3 Hz), 1.90–1.76 (m,
2H), 1.25 (d, 3H, J = 6.2 Hz); 13C NMR (75 MHz,
CDCl3): 174.81, 133.86, 129.69, 73.98, 72.49, 72.11,
68.28, 43.04, 33.33, 21.23; IR (KBr) 3414, 2925, 2855,
1708, 1042 cmꢀ1; HRMS: Calcd m/z 239.0895 (C10H16-
O5Na). Found m/z 239.0906, ppm error 4.4186. Literature
data2 of compound 1: [a]D ꢀ67.0 (c 0.26, CHCl3) [lit.1b
[a]D ꢀ62.0 (c 0.4, CHCl3)]; mp = 118–120 ꢁC (lit.1b mp)
CHCl3); 1H NMR (200 MHz, CDCl3): d 7.25–7.22 (m,
15H), 5.69–5.67 (m, 2H), 4.62 (br s, 2H), 4.56 (d, 1H,
J = 3.4 Hz), 4.50 (d, 1H, J = 3.0 Hz), 4.40–4.27 (m, 2H),
4.07–3.99 (m, 4H), 2.67 (dd, 1H, J = 3.8, 15.9 Hz), 2.47
(dd, 1H, J = 7.6, 15.9 Hz), 1.69–1.63 (m, 2H), 1.15 (d, 3H,
J = 6.0 Hz); 13C NMR (75 MHz, CDCl3): 176.04, 138.12,
138.04, 134.95, 129.02, 128.61, 128.52, 128.44, 128.00,
127.83, 80.03, 79.65, 77.61, 77.53, 73.39, 71.04, 70.72,
64.93, 43.95, 36.22, 29.81, 23.47; IR (thin film) 3448, 2923,
2855, 1714, 1096 cmꢀ1
;
ESIMS; 505 (M+H)+, 527
(M+Na)+. Anal. Calcd for C31H36O6: C, 73.79; H, 7.19.
1
Found: C, 73.71; H, 7.22%. Compound 18: Thick syrup;
114–115 ꢁC; H NMR: d 5.91 (dd, 1H, J = 15.8, 8.3 Hz),
25
1
½aꢁD ꢀ6:1 (c 0.6, CHCl3); H NMR (400 MHz, CDCl3): d
7.34–7.17 (m, 15H), 5.84 (dd, 1H, J = 9.6, 16.2 Hz), 5.68
(dd, 1H, J = 2.7, 15.9 Hz), 5.13–5.08 (m, 1H), 4.82 (d,
1H, J = 11.6 Hz), 4.62 (d, 1H, J = 12.0 Hz), 4.53 (d,
1H, J = 5.0 Hz), 4.50 (d, 1H, J = 5.4 Hz), 4.41 (d, 1H,
J = 12.0 Hz), 4.30 (d, 1H, J = 12.0 Hz), 4.06 (t, 1H,
J = 3.1 Hz), 3.90–3.81 (m, 2H), 2.55 (dd, 1H, J = 2.1,
13.9 Hz), 2.46 (dd, 1H, J = 6.9, 13.9 Hz), 1.91–1.82 (m,
2H), 1.21 (d, 3H, J = 6.2 Hz); 13C NMR (75 MHz,
CDCl3): 171.25, 138.02,137.56, 134.45, 129.00, 127.91,
5.85 (dd, 1H, J = 15.8, 2.4 Hz), 5.25 (ddq, 1H, J = 14.0,
6.4, 1.9 Hz), 4.54–4.78 (br s, 1H), 4.43 (dd, 1H, J= 3.7,
1.6 Hz), 4.20 (ddd, 1H, J = 11.0, 8.3, 4.0 Hz), 3.94–4.13
(br s, 1H), 2.61 (d, 1H, J = 14.4, 1.9 Hz), 2.40 (d, 1H,
J = 14.4, 6.2 Hz), 1.92 (ddd, 1H, J = 14.0,4.0, 1.9 Hz),
1.81 (d, 1H, J= 14.0, 11.0 Hz), 1.52–1.72 (br s, 2 · OH),
1.25 (d, 3H, J = 6.4 Hz); 13C NMR: d 174.9, 133.7, 129.9,
73.9, 72.5, 72.2, 68.2, 43.0, 33.2, 21.3 (lit.1b (CD3OD)
174.7, 135.9, 129.4, 75.4, 73.6, 73.1, 69.4, 44.2, 35.6,
21.6).