Stereoselective synthesis of the enantiomer of the key fragment of crocacin

Article abstract of DOI:10.1016/j.tetlet.2004.05.130

A novel, stereoselective synthesis of the enantiomer of alcohol 5 is disclosed. The key steps of the synthesis include mercuric trifluoroacetate promoted regio- and stereoselective hydration of an α,β-unsaturated ester, Frater-alkylation and use of morpho

Full text of DOI:10.1016/j.tetlet.2004.05.130

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5593–5595
Stereoselective synthesis of the enantiomer of the key fragment
of crocacinq
Sadagopan Raghavan* and S. Ramakrishna Reddy
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 21 April 2004; accepted 27 May 2004
Abstract—A novel, stereoselective synthesis ofthe enantiomer ofalcohol 5 is disclosed. The key steps ofthe synthesis include
mercuric trifluoroacetate promoted regio- and stereoselective hydration ofan a,b-unsaturated ester, Frater-alkylation and use of
morpholine derived amide for acylation.
Ó 2004 Elsevier Ltd. All rights reserved.
Crocacins A–D 1–4, isolated from myxobacteria
Chondromyces crocatus and C. pediculatus1 possess
antibacterial, antifungal and cytotoxic activity. Crocac-
ins possess four contiguous chiral centres flanked by two
trans double bonds in addition to a trisubstituted and cis
double bonds. Their novel architecture and biological
activity has attracted the attention ofsynthetic chemists
and stereoselective routes to crocacin C,2 crocacin D3
and crocacin A4 have been described. An advanced
common intermediate for the synthesis of all the cro-
cacins is the alcohol 5, the synthesis ofwhich was also
disclosed recently.5 We describe herein a stereoselective
synthesis ofthe enantiomer 6 ofalcohol 5 with the
(2R,3R,4S,5R) configuration.
7, which in turn could be prepared from the amide 8 by
acylation. The amide 8 could be traced back to the hy-
droxy ester 9, which could be derived from the (Z)- or
(E)-a,b-unsaturated ester 10 or 11, respectively.
The aldehyde 126 can be readily transformed into the
(Z)-6 and (E)-esters7 in high yield. The hydroxy ester 9
can be prepared from 10 in two steps as described ear-
lier.6 This would warrant the use oftoxic n-Bu3SnH for
debromination. To avoid the use of n-Bu3SnH, reagents
other than NBS were contemplated for the electrophile
promoted functionalisation of esters 10 and 11. In the
event, treatment ofester 11 with mercuric trifluoroace-
tate in the presence ofwater in toluene, afforded the
hydroxy ester 9 after demercuration of the organomer-
curial with NaBH4.8 This constitutes the first report on
the heterofunctionalisation of an alkene mediated by
By a retrosynthetic analysis (Scheme 1) we envisaged
alcohol 6 to be elaborated from the unsaturated ketone
Me Me
8
NH2
5
Me Me
10
NH
1
OR
OMe OMe
3 Crocacin C
Me
O
19
17
O
N
21
15
H
OMe OMe
Me
O
O
1 Crocacin A; R = Me; C5-C6 = double bond
2 Crocacin B; R = H; C5-C6 = double bond
4 Cocacin D; R = Me; C5-C6 = single bond
Me Me
S
OH
R
S
S
OMe OMe
5
Keywords: Crocacin; Mercuric trifluoroacetate; Frater-alkylation.
q IICT Communication No. 040321.
* Corresponding author. Tel.: +91-(0)-4027160123; fax: +91-(0)-4027160512; e-mail: purush101@yahoo.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.130

5594
S. Raghavan, S. Ramakrishna Reddy / Tetrahedron Letters 45 (2004) 5593–5595
Me Me
R
Me Me
Me Me
R
HO
PhS
PhS
NR2
R
S
OMe OMe
OH
O
OH
O
7
6
8
O
S
Me
O
S
Me R1
OEt
R2
Ph
Ph
OH
O
10, R1 = CO2Et, R2 = H
11, R1 = H, R2 = CO2Et
9
Scheme 1.
mercuric trifluoroacetate via intramolecular sulfinyl
group participation. The inseparable mixture ofepi-
meric sulfoxides 9 yielded sulfone 13 on oxidation with
reduction of 7 with Me4N(OAc)3BH16 yielded the anti
diol 20 cleanly.17 The structure assigned to 20 was based
on literature precedent and was proven by its elabora-
tion to 6. Thus treatment of 20 with NaHMDS and
methyl iodide yielded the dimethoxy derivative 21.
Oxidation ofsulfide 21 with NaIO418 yielded an epimeric
mixture ofsulof xides 22 in nearly equimolar amounts.
Sulfoxide 22 on treatment with TFAA and Et3N
underwent Pummerer rearrangement to yield interme-
diate 23, which without isolation was subjected to
hydrolysis followed by reduction to yield the alcohol 6,
which had physical characteristics in excellent agree-
ment to those reported in the literature for 5 except for
1
m-CPBA, the H NMR spectrum ofwhich revealed the
presence ofstereomers in a 18:1 ratio. The ( Z)-ester 10
reacted under identical conditions to yield the products
in the same ratio. The reaction can be envisaged to
proceed via intermediates I and II9 to afford the or-
ganomercurials III and IV, which on demercuration
would yield the products (Scheme 2). The intermediate
II with an axially disposed Me group would probably
explain the erosion ofstereoselectivity. The ester 11 was
chosen as the starting material since it can be more
readily prepared from aldehyde 12 than ester 10.
the sign ofrotation, ½aŠ25 +6.0 (c 0.5, CHCl3), literature2c
D
25
D
½aŠ )6.5 (c 1, CHCl3) (Scheme 3).
The C4 methyl group ofcrocacin was envisaged to be
introduced by Frater-alkylation.10 To avoid alkylation
at C1 the sulfinyl group in 9 was reduced by treatment
In summary we have described a novel, stereoselective
synthesis ofthe advanced intermediate 6, which can be
elaborated into the enantiomer ofcrocacins by following
earlier reports. The key steps ofthe synthesis include the
use ofmercuric trifluoroacetate as the electrophilic
partner in the regio- and stereoselective hydration ofthe
ester 11 via intramolecular nucleophilic assistance by the
sulfinyl group, Frater-alkylation, use ofthe morpholine
amide for acylation and the Pummerer reaction for the
introduction ofthe hydroxy group. The strategy dis-
closed is flexible and would permit the preparation of
derivatives for structure activity relationship studies by
varying the electrophile in the Frater-alkylation step and
the nucleophile used for the acylation.
11
with TiCl3 to yield the sulfide 14.12 Treatment ofthe
dianion of 14, derived by treatment with LDA, with
methyl iodide yielded compound 15 and its stereomer
(not depicted) in a 4:1 ratio, respectively.13 This mixture
was taken ahead with the hope ofremoving the unde-
sired stereomer at a later stage in the synthesis. Com-
pound 15 on mild hydrolysis by treatment with aq LiOH
yielded the acid 16, which was converted to the amide 17
by treatment with morpholine and diisopropyl carbo-
diimide (DIC). Treatment of 17 with vinyl lithium 19
generated from the unsaturated stannane 18,14 yielded
the unsaturated ketone 7.15 Hydroxy group directed
H2O
R1
R1
O
Me
HgOCOCF3
R2
O
S
Me R1
O
S
Me
a (i)
S
Ph
O
a (ii)
S
OEt
R2
R2
Ph
Ph
Ph
Me
HgOCOCF3
OH
OH
9a
O
10a, R1 = CO2Et, R2 = H
11a, R1 = H, R2 = CO2Et
III
I
b
b
O
S
Me
Me
S
OEt
OEt
Ph
O
Ph
OH
O
O
12
13
R1
R1
O
S
Me R1
Ph
S
O
Me
O
S
Me
HgOCOCF3
R2
H2O
a (i)
O
a (ii)
R2
HgOCOCF3
S
R2
Ph
Ph
Ph
OH
OH
O
Me
10b, R1 = CO2Et, R2 = H
11b, R1 = H, R2 = CO2Et
9b
IV
II
Scheme 2. Reaction conditions: (a) i. Hg(OCOCF3)2, HgO, toluene, rt, ii. Et3B, NaBH4, )78 °C to rt, 75%; (b) m-CPBA, DCM, rt, 90%.

S. Raghavan, S. Ramakrishna Reddy / Tetrahedron Letters 45 (2004) 5593–5595
5595
Y
X
Me
Me Me
Me Me
b
e
PhS
OEt
PhS
c
R
PhS
OH
O
OH
O
OH
O
9 X =
14 X = Y =
; Y = O
15 R = OEt
16 R = OH
7
a
d
17 R =
N
O
Me Me
O
Me Me
i
h
PhS
PhS
f
(i)
OP OP1
OMe OMe
22
20 P = P1 = H
g
21 P = P1 = Me
Me Me
Me Me
R
Ph
PhS
i
M
R
HO
R
S
(ii)
18 M = SnBu3
19 M = Li
CF3C(O)O
OMe OMe
23
OMe OMe
6
Scheme 3. Reaction conditions: (a) TiCl3, EtOH, rt, 85%; (b) LDA, THF, )78 to )23 °C, MeI, HMPA, )78 to )23 °C, 75%; (c) LiOH, MeOH, THF,
0 °C, 90%; (d) morpholine, DIC, DMAP, DCM, rt, 70%; (e) 18, n-BuLi, THF, )78 °C, 80%; (f) Me4NB(OAc)3H, CH3CN, AcOH, rt, 85%;
(g) NaHMDS, THF, 0 °C, MeI, 80%; (h) NaIO4, MeOH, THF, rt, 80%; (i) i. TFAA, Et3N, CH3CN, rt, ii. aq NaHCO3, NaBH4, 0 °C, 75%.
9. Treatment ofester 10 with mercuric trifluoroacetate in the
presence ofH 218O yielded sulfoxide 23 with (m=z 286) two
units higher than 9 (m=z 284). Subsequent reduction ofthe
sulfinyl moiety yielded sulfide with the loss of18 mass
units conclusively proving intramolecular sulfinyl group
participation.
Acknowledgements
S.R. is thankful to Dr. J. S. Yadav for constant support
and encouragement, to Dr. A. C. Kunwar for NMR
spectra and Dr. M. Vairamani for the mass spectra.
S.R.R. is thankful to CSIR (New Delhi) for the senior
research fellowship.
18O
Me
Me
O
S
Me
Hg(OCOCF3)2O, HgO
TiCl3
S
OEt
S
OEt
Ph
Ph
Ph
CO2Et
H218O
OH
23
m/z = 286
O
OH
13
m/z = 268
O
10
NaBH4, Et3B
Also while 9 showed a peak at 126 mass units correspond-
ing to [PhSOH]þ fragment in its mass spectrum, 23 showed
a peak at 128 mass units.
References and notes
1. (a) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H.
J. Antibiot. 1994, 47, 1075; (b) Jansen, R.; Washausen, P.;
Kunze, B.; Reichenbach, H.; Hofle, G. Eur. J. Org. Chem.
1999, 1085.
2. (a) Feutrill, J. T.; Lilly, M. J.; Rizzacasa, M. A. Org. Lett.
2000, 2, 3365; (b) Chakraborty, T. K.; Jayaprakash, S.
Tetrahedron Lett. 2000, 42, 497; (c) Chakraborty, T. K.;
Jayaprakash, S.; Laxman, P. Tetrahedron 2001, 57, 9461;
(d) Dias, L. C.; de Oliveira, L. G. Org. Lett. 2001, 32,
3951.
3. Chakraborty, T. K.; Laxman, P. Tetrahedron Lett. 2003,
44, 4989.
4. (a) Feutrill, J. T.; Lilly, M. J.; Rizzacasa, M. A. Org. Lett.
2002, 4, 525; (b) Chakraborty, T. K.; Laxman, P.
Tetrahedron Lett. 2002, 43, 2645.
10. (a) Frater, G. Helv. Chim. Acta 1979, 62, 2825; (b) Frater,
G.; Muller, U.; Gunther, W. Tetrahedron 1984, 40, 1269.
11. Takahashi, T.; Iyobe, A.; Arai, Y.; Koizumi, T. Synthesis
1989, 189.
12. After column chromatography of the crude product
mixture, 13 was obtained pure without any trace ofthe
stereoisomer.
13. The structure was assigned to the major product based on
literature precedent, which was confirmed by the synthesis
of 5.
14. Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem.
1983, 48, 4634.
15. Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J.
Synlett 1997, 1414.
16. Evans, D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L.
Tetrahedron 1992, 48, 2127.
17. The minor stereomer from the Frater-alkylation reaction
could be conveniently removed by purification by column
chromatography.
5. Gurjar, M. K.; Khaladkar, T. P.; Borhade, R. G.;
Murugan, A. Tetrahedron Lett. 2003, 44, 5183.
6. Raghavan, S.; Tony, K. A. J. Org. Chem. 2003, 68, 5002.
7. Raghavan, S.; Tony, K. A. Tetrahedron Lett. 2004, 45,
2639.
18. Leonard, N. J.; Johnson, C. R. J. Org. Chem. 1962, 27,
282.
8. Kang, S. H.; Lee, J. H.; Lee, S. B. Tetrahedron Lett. 1998,
39, 59.