Synthesis of C15-C27 segment of venturicidine X by utilizing desymmetrization protocol

Article abstract of DOI:10.1016/j.tetlet.2010.05.148

We have achieved the synthesis of C15-C27 fragment of venturicidine X using desymmetrization protocol, substrate-controlled Grignard reaction, Barton-McCombie reaction, Sharpless epoxidation, and TBSOTf-mediated rearrangement to produce the aldol product

Full text of DOI:10.1016/j.tetlet.2010.05.148

Tetrahedron Letters 51 (2010) 4179–4181
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Tetrahedron Letters
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Synthesis of C15–C27 segment of venturicidine X by utilizing
desymmetrization protocol
*
J. S. Yadav , Sk. Samad Hossain, Debendra K. Mohapatra
Organic Chemistry Division-I, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We have achieved the synthesis of C15–C27 fragment of venturicidine X using desymmetrization proto-
col, substrate-controlled Grignard reaction, Barton–McCombie reaction, Sharpless epoxidation, and
TBSOTf-mediated rearrangement to produce the aldol product through a non-aldol route as the key step
following 23 longest linear sequences with 6.4% overall yield starting from a known intermediate 11.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 28 April 2010
Revised 27 May 2010
Accepted 29 May 2010
Available online 4 June 2010
Keywords:
Venturicidines A, B, and X
Desymmetrization
Barton–McCombie reaction
Wittig reaction
Sharpless asymmetric epoxidation
27
Venturicidines A, B, and its aglycone venturicidine X, 20-mem-
bered macrolide antibiotics, were isolated from several streptomy-
ces.1 Their structures and absolute configurations ( Fig. 1) were
elucidated by chemical degradations, spectroscopic correlation,
and X-ray crystallographic analysis.2 They exhibit strong activity
against a number of plant pathogenic fungi and mitochondrial
H+ATPase.3 In 1990, Akita et al. accomplished the first total synthe-
sis and determination of absolute stereochemistry of the aglycone
of venturicidines A and B.4 Encouraged by the interesting chemical
structure combined with remarkable biological activities, we
decided to apply our developed desymmetrization protocol and
herein we present a highly stereocontrolled synthesis of C15–C27
segment4b,5 of venturicidine X.
Retrosynthetic analysis revealed that venturicidine X can be di-
vided into two major segments C1–C14 (2) and C15–C27 (3), which
could be coupled by esterification followed by Wittig–Horner con-
densation. Fragment 3 would be obtained from the intermediate 4
by Sharpless asymmetric epoxidation followed by TBSOTf-medi-
ated rearrangement to produce the aldol product by a non-aldol
route as the key reaction. Intermediate 4 would be obtained from
5 following standard reaction procedure. The intermediate 5 could
be obtained from a known bicyclic lactone 6 employing acid-cata-
lyzed methanolysis and substrate-controlled Grignard reaction as
key steps. The bicyclic lactone 6 would be obtained by utilizing
14
RO
15
O
O
OH
O
1
O
H
OH
Venturicidine X (1)
R = H
OH
OH
H2NCOO
R =
HO
R =
O
O
Venturicidine A
Venturicidine B
Figure 1. Structures of venturicidines A, B, and its aglycone venturicidine X.
desymmetrization technique to create six contiguous chiral cen-
ters (Scheme 1).
The exo-alkylated lactone 66 was obtained by the following
sequence, Zn–Cu couple-mediated (ꢀ10 °C) [4+3] cycloaddition
reaction between 2,4-dibromopentan-3-one and furan to form
2,4-dimethyl-8-oxabicyclo-[3.2.1]-oct-6-ene-3-ones 7,7 DIBAL-H
reduction 8, benzyl protection 9, asymmetric hydroboration 10,
PCC mediated oxidation, Bayer–Villiger reaction,8 and alkylation
* Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160387.
E-mail addresses: yadavpub@iict.res.in (J.S. Yadav), mohapatra@iict.res.in (D.K.
Mohapatra).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.148

4180
J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 4179–4181
27
P(O)(OMe)2
14
27
HO
O
14
15
O
O
OH
O
15
OTBDMS OH
1
COOH
1
+
O
O
O
O
H
OH
3
H
OMe
2
O
Br
Br
MeO
O
EtOOC
O
+
O
O
OH
O
O
O
6
OBn
4
OBn
5
Scheme 1. Retrosynthetic analysis of venturicidine X.
6. Acid-catalyzed methanolysis,9 lithium aluminum hydride (LAH)-
mediated reduction, and IBX10-mediated oxidation afforded the
aldehyde 11.11 Substrate-controlled Grignard reaction12 with ethyl
magnesium bromide in THF afforded the desired Felkin–Anh13
alcohol 514 (89%) as the major product (93:7 by HPLC) (Fig. 2).
The absolute stereochemistry of the newly generated chiral center
was confirmed in the later stage of the synthesis.15 Acetylation of 5
with acetic anhydride furnished 12 (95%) (Scheme 2).
Compound 12 upon treatment with 60% aqueous acetic acid at
60 °C followed by TEMPO-BAIB-mediated oxidation16 afforded 13
(76% over two steps). The axial methyl center was isomerized to
equatorial using DBU as the base to obtain 14 and upon treatment
with LAH in THF provided triol 15 (80% over two steps). Acetonide
protection of 15 followed by catalytic hydrogenation using Pd–C
afforded 1617 (76% over two steps). The primary hydroxyl group
was selectively protected with TBDMSCl and imidazole to afford
17 (90%) and the secondary hydroxyl group was converted to its
xanthate derivative 18 (87%) which on subsequent treatment with
Bu3SnH18 in the presence of a catalytic amount of AIBN in refluxing
benzene afforded 19 (92%). Desilylation of the primary hydroxyl
group using TBAF in THF at room temperature afforded 20 (91%)
(Scheme 3).
LDA in the presence of MeI at ꢀ78 °C provided 25 (85%). Reduction
of lactone 25 with LAH in THF afforded diol which on selective pro-
tection with TBDMSCl and imidazole afforded the desired C15–C27
segment 3 of venturicidine X in 95% yield (Scheme 4). The spectral
and analytical data of 323 were identical with the literature
reported values.
In conclusion, we have achieved the synthesis of C15–C27
polyketide back bone of venturicidine X using desymmetrization
protocol, substrate-controlled Grignard reaction, Barton–
McCombie reaction, Wittig reaction, Sharpless epoxidation, and
TBSOTf-mediated rearrangement to produce an aldol product
through a non-aldol route as the key step following 23 longest liner
sequences with 6.4% overall yield starting from a known interme-
diate 11.
O
Br
Br
a
isomeric
ketones
O
+
+
O
7
O
O
c
b
isomeric alcohols
+
IBX oxidation of 20 in DMSO and THF furnished aldehyde,
which on Wittig homologation with Ph3P@C(Me)COOEt in reflux-
ing benzene afforded a,b-unsaturated ester 4 (77% over two steps)
8
OH
O
O
favoring the desired E-isomer. DIBAL-H reduction of the ester affor-
ded the corresponding allylic alcohol. Sharpless asymmetric epox-
idation19 proceeded efficiently to produce epoxide 21 (78% over
two steps) which upon treatment with TBSOTf and N,N-diisopro-
pylethylamine furnished a rearranged aldehyde 22 (76%) with
good selectivity.20 Wittig homologation of aldehyde 22 with
Ph3P@CHCOOEt in refluxing benzene (89%) followed by catalytic
hydrogenation with Pd–C afforded 2321 (96%) and further lacton-
ization in the presence of PPTS in CH2Cl2/MeOH (10:1) furnished
24 (86%). Diastereoselective methylation22 of lactone 24 with
desymmetrization
d
e, f
HO
10
9
OBn
OBn
O
MeO
O
g
h
CHO
O
O
6
11
OBn
OBn
MeO
O
MeO
O
i
OAc
OH
O
Me
Et
Me
OH
OBn
12
OBn
5
Scheme 2. Reagents and conditions: (a) Zn–Cu couple, DME, ꢀ10 °C, 6 h, 82%; (b)
DIBAL-H, CH2Cl2, ꢀ10 °C, 1 h, 74% (required product); (c) NaH, BnBr, THF, 50 °C,
94%; (d) (ꢀ)-(Ipc)2BH, THF, ꢀ20 °C, 5 days, 92%; (e) (1) PCC, CH2Cl2, rt, 3 h, 90%; (2)
m-CPBA, NaHCO3, CH2Cl2, rt, 90%; (f) LDA, MeI, THF, ꢀ78 °C, 1 h, 94%; (g) (1) LAH,
THF, 0 °C to rt, 12 h, 89%; (2) IBX, DMSO, THF, rt, 6 h, 95%; (h) EtMgBr, THF, ꢀ78 °C,
1 h, 89%; (i) Ac2O, Et3N, CH2Cl2, rt, 1 h, 95%.
H
H
H
H
EtMgBr
major alcohol
favoured
attuck
Figure 2. Felkin–Anh model for the formation of 5.

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 4179–4181
4181
Supplementary data
MeO
O
O
O
a, b
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.148.
OAc
OAc
OBn
12
OBn
13
References and notes
O
O
d
c
1. (a) Rhodes, A.; Fantes, K. H.; Boothroyd, B.; McGonagle, M. P.; Crosse, R. Nature
1961, 192, 952; (b) Laatsch, H.; Kellner, M.; Lee, Y.-S.; Wolf, G. Z. Nature-forsch.
1994, 49b, 977.
2. (a) Brufani, M.; Keller-Schierlein, W.; Löffler, W.; Mansperger, I.; Zähner, H.
Helv. Chim. Acta 1968, 51, 1293; (b) Brufani, M.; Cerrini, S.; Fedeli, W.; Musu, C.;
Cellai, L.; Keller-Schierlein, W. Experientia 1971, 27, 604; (c) Brufani, M.; Cellai,
L.; Musu, C.; Keller-Schierlein, W. Helv. Chem. Acta 1972, 55, 2329.
3. (a) Linnet, P. E.; Beekey, R. B. Methods Enzymol. 1979, 55, 472; (b) Lardy, H. A.
Pharmacol. Ther. 1980, 11, 649.
4. (a) Akita, H.; Yamada, H.; Matsukura, H.; Nakata, T.; Oishi, T. Tetrahedron Lett.
1990, 31, 1731; (b) Akita, H.; Yamada, H.; Matsukura, H.; Nakata, T.; Oishi, T.
Tetrahedron Lett. 1990, 31, 1735.
5. (a) Hoffmann, R. W.; Rolle, U. Tetrahedron Lett. 1994, 35, 4751; (b) Tsunashima,
K.; Ide, M.; Kadoi, H.; Hirayama, A.; Nakata, M. Tetrahedron Lett. 2001, 42, 3607;
(c) Hoffmann, R. W.; Rolle, U.; Göttlich, R. Liebigs Ann. 1996, 1717.
6. Rama Rao, A. V.; Yadav, J. S.; Vidyasagar, V. J. Chem. Soc., Chem. Commun. 1985,
55.
OAc
OH OBn OH OH
OBn
14
15
g
e, f
OR1
OR1 OR2
O
O
O
O
16. R1 = R2 = H
1
19.
20.
R = TBDMS
h
i
R = TBDMS, R2 = H
1
j
1
17.
R = H
18. R1 = TBDMS, R2 = Xanthate
Scheme 3. Reagents and conditions: (a) 60% AcOH/H2O, 60 °C, 3 h, 82%; (b) TEMPO,
BAIB, CH2Cl2, rt, 3 h, 93%; (c) cat. DBU, CH2Cl2, 4 h, 90%; (d) LAH, THF, rt, 2 h, 89%; (e)
2,2-DMP, p-TsOH, CH2Cl2, rt, 6 h, 85%; (f) H2, Pd–C (10%), hexane, 12 h, 89%; (g)
TBDMSCl, Imid, CH2Cl2, 2 h, 0 °C, 90%; (h) NaHMDS, CS2, MeI, THF, ꢀ78 °C, 1 h, 87%;
(i) Bu3SnH, AIBN, PhH, 80 °C, 3 h, 92%; (j) TBAF, THF, rt, 2 h, 91%.
7. Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984, 23, 1.
8. Corey, E. J.; Weinshenker, N. M.; Schoff, T. F.; Hubber, W. J. J. Am. Chem. Soc.
1969, 91, 5675.
9. Yadav, J. S.; Venkatram Reddy, P.; Chandraiah, L. Tetrahedron Lett. 2007, 48, 145.
10. Frigeno, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
11. Yadav, J. S.; Hossain, S. S.; Madhu, M.; Mohapatra, D. K. J. Org. Chem. 2009, 74,
8822.
12. Christoffers, J.; Scharl, H.; Frey, W.; Baro, A. Org. Lett. 2004, 6, 1171.
13. (a) Anh, N. T. Top. Curr. Chem. 1980, 88, 145; (b) Mulzar, J. Nachr. Chem. Tech.
Lab. 1984, 32, 16.
a, b
c, d
f, g
EtOOC
14. Spectral and analytical data of 5: ½a D27
ꢁ
+37.0 (c 1.4, CHCl3); IR (neat):
m
max 3498,
2969, 2933, 2851, 1459, 1354, 1259, 1209, 1183, 1132, 1078, 1043 cmꢀ1
;
1H
O
O
O
O
O
OH
OH
NMR (300 MHz, CDCl3) d 7.36–7.17 (m, 5H), 4.51 (s, 1H), 4.49 (s, 2H), 3.87–3.77
(m, 3H), 3.36 (s, 3H), 2.18 (m, 1H), 2.06 (tdd, J = 12.2, 6.7, 2.6 Hz, 1H), 1.82 (tdd
J = 13.9, 6.9, 1.8 Hz, 1H), 1.70 (d, J = 5.6 Hz, 1H), 1.57–1.36 (m, 2H), 1.05 (d,
J = 7.5 Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H), 0.97 (d, J = 7.1 Hz, 3H), 0.77 (d, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 138.9, 128.2, 127.3, 127.1, 104.8, 75.3, 73.4,
70.9, 69.3, 55.4, 38.2, 36.5, 33.4, 26.9, 13.2, 10.9, 9.3, 7.7; HRMS: m/z calcd for
4
20
e
OHC
C20H32O4 337.2378; found 337.2368.
O
15. (a) The value 100.61 ppm, 100.04 ppm, 100.15 ppm in 13C NMR for compounds
12, 19, 3 indicate newly generated OH at C25 is anti with respect to C23-OH.;
(b) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511.
16. Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.; Abrams, J. N.; Forsyth, C. J.
Tetrahedron Lett. 2003, 44, 57.
O
OTBDMS
O
O
21
22
17. Spectral and analytical data of 17: ½a D27
ꢁ
ꢀ5.3 (c 1.5, CHCl3); IR (neat):
m
max 3522,
EtOOC
2933, 2960, 1463, 1380, 1253, 1224, 1154, 1088, 1017 cmꢀ1
;
1H NMR
i
h
(300 MHz, CDCl3) d 3.74–3.56 (m, 5H), 3.08 (d, J = 2.83 Hz, 1H), 1.88–1.64 (m,
2H), 1.61 (tdd, J = 14.7, 6.7, 2.07 Hz, 1H), 1.50–1.24 (m, 2H), 1.33 (s, 3H), 1.29 (s,
3H), 0.98–0.86 (m, 6H), 0.90 (s, 9H), 0.84 (d, J = 7.2 Hz, 3H), 0.83 (d, J = 6.7 Hz,
3H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3) d 100.6, 75.0, 74.4, 71.6, 68.1, 38.6,
37.3, 35.9, 26.1, 25.4, 23.9, 23.9, 18.5, 12.4, 11.1, 10.7, 9.9, ꢀ5.3; ESIMS: m/z
[M+Na]+ 412.
O
O
O
O
O
O
OTBDMS
24
23
18. Barton, D. H. R.; Hartwig, W.; Motherwell, R. S. H.; Motherwell, W. B.; Stange, A.
Tetrahedron Lett. 1982, 23, 2019.
j, k
19. Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
20. Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115, 12208.
21. Spectral and analytical data of 23: ½a D27
ꢁ
+21.7 (c 1.7, CHCl3); IR (neat) m
max 2961,
O
O
O
OTBDMS OH
O
O
2933, 2883, 1736, 1462, 1377, 1253, 1224,1176, 1093, 1023 cmꢀ1
;
1H NMR
O
25
3
(300 MHz, CDCl3) d 4.10 (q, J = 7.2 Hz, 2H), 3.58 (dt, J = 9.3, 5.2 Hz, 1H), 3.30 (dd,
J = 5.2, 3.1 Hz, 1H), 3.06 (dd, J = 7.2, 3.1 Hz, 1H), 2.35–2.18 (m, 2H), 1.76–1.36
(m, 8H), 1.35–1.28 (m, 1H), 1.27 (s, 6H), 1.26 (t, J = 7.2 Hz, 3H), 1.06–0.98 (m,
1H), 0.90 (s, 9H), 0.94–0.79 (m, 15H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 173.9, 100.0, 79.9, 79.0, 71.1, 60.2, 36.7, 36.5, 35.6, 34.8,
33.7, 32.7, 30.5, 26.2, 25.3, 23.6, 18.4, 16.1, 14.2, 13.5, 12.5,10.5, 1.0, ꢀ3.8;
ESIMS: m/z [M+Na]+ 523.
Scheme 4. Reagents and conditions: (a) IBX, DMSO, THF, rt, 2 h, 92%; (b)
Ph3P@C(Me)COOEt, benzene, 80 °C, 3 h, 84%; (c) DIBAL-H, CH2Cl2, ꢀ78 °C, 1 h,
0
93%; (d) tBuOOH, Ti(OiPr)4,
D
-(ꢀ)-DET, 4 ÅA MS, ꢀ20 °C, 12 h, 84%; (e) TBSOTf, DIPEA,
0
4 ÅA MS, –40 °C, 76%; (f) Ph3P@CHCOOEt, benzene, 80 °C, 4 h, 89%; (g) H2, Pd–C
(10%), EtOAc, 3 h, 96%; (h) PPTS, CH2Cl2/MeOH (10:1), 0 °C, 5 h, 86%; (i) LDA, MeI,
ꢀ78 °C, 1 h, 85%; (j) LAH, THF, 0 °C to rt, 1 h, 92%; (k) TBDMSCl, Imid, CH2Cl2, 0 °C,
1 h, 95%.
22. Miyashit, M.; Toshimitsu, Y.; Shiratni, T.; Iri, H. Tetrahedron: Asymmetry 1993, 4,
1573.
23. Spectral and analytical data of 3: ½a D27
ꢁ
+35.0 (c 1.2, CHCl3); IR (neat) mmax 3503,
2958, 2925, 2855, 1462, 1378, 1251, 1225, 1177, 1153, 1094, 1016 cmꢀ1
;
1H
NMR (600 MHz, CDCl3) d 3.63 (ddd, J = 9.1, 4.8, 4.6 Hz, 1H), 3.44 (dd, J = 9.7,
4.8 Hz, 1H), 3.37 (dd, J = 9.7, 6.4 Hz, 1H), 3.16–3.11 (m, 2H), 1.81–1.51 (m, 7H),
1.48–1.33 (m, 3H), 1.32 (s, 3H), 1.30 (s, 3H), 1.27–1.17 (m, 1H), 1.10 (ddd,
J = 13.4, 9.5, 4.4 Hz, 1H), 0.90 (s, 9H), 0.94–0.82 (m, 18H), 0.04 (s, 6H); 13C NMR
(150 MHz, CDCl3) d 100.2, 80.0, 79.2, 71.2, 69.0, 37.6, 36.1, 35.0, 33.5, 33.4, 33.1,
32.0, 25.9, 25.3, 23.6, 18.3, 16.5, 16.0, 14.7, 12.9, 12.7, 10.5, -5.3; ESIMS: m/z
[M+Na]+ 496.
Acknowledgment
S.S.H. thanks Council of Scientific and Industrial research (CSIR),
New Delhi, for the financial assistance in the form of research
fellowships.