Stereoselective formal synthesis of crocacin C via prins cyclization

Article abstract of DOI:10.1055/s-2007-984896

A formal synthesis of crocacin C is described proving the versatility of Prins cyclization in natural product synthesis. The approach is convergent and highly stereoselective. Cross-metathesis and Heck reactions were utilized for the insertion of an aroma

Full text of DOI:10.1055/s-2007-984896

LETTER
2049
Stereoselective Formal Synthesis of Crocacin C via Prins Cyclization
S
tereosele
.
ctive
F
ormal
S
Synthesis of
C
.
rocacin
C
Yadav,* M. Sridhar Reddy, P. Purushothama Rao, A. R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 6 October 2006
The Prins cyclization has been emerged as a powerful
synthetic tool for the construction of polysubstituted
tetrahydropyran systems and has been utilized in the
synthesis of several natural products.4–6 We recently
extended the use of Prins cyclization in the synthesis of
various polyketide intermediates and explored its applica-
tion in the synthesis of some natural products.6 In this
paper, we report the synthesis of crocacin C through Prins
cyclization.
Abstract: A formal synthesis of crocacin C is described proving the
versatility of Prins cyclization in natural product synthesis. The
approach is convergent and highly stereoselective. Cross-metathe-
sis and Heck reactions were utilized for the insertion of an aromatic
group in a stereocontrolled manner.
Key words: crocacins, Prins cyclization, olefin rearrangement,
cross-metathesis
The crocacins A (1), B (2), C (3), and D (4) are a group of
electron-transport inhibitors isolated from myxobacteria
belonging to the chondromyces genus.1 Compounds 1–4
moderately inhibit the growth of a few gram-positive
bacteria and are potent inhibitors of animal cell cultures
and several yeasts and fungi.1b The crocacins represent a
second novel group of modified peptides from C. crocatus
and are linear dipeptides unlike the chondramides isolated
earlier.2 Crocacin C (3) is a structural fragment of cro-
cacins A, B, and D (Scheme 1). Synthetic efforts3 towards
crocacins A, B, and D were significantly influenced by the
synthesis of structural intermediate crocacin C, which
could then be elaborated to install variable side chains.
We describe herein a stereoselective formal synthesis of
crocacin C via Prins cyclization.
By a retrosynthetic analysis (Scheme 1) we envisaged that
crocacin C would be easily constructed from alcohol 5.
Alcohol 5 would be elaborated from a suitably substituted
pyran system 6 with all required stereogenic centers along
with a hydroxy methyl group at C-6, which would be
utilized in the opening of the pyran ring. Pyran 6 was to be
assembled through Prins cyclization from homoallylic
alcohol 7 and aldehyde 8 which in turn could be obtained
through well-established literature procedures.
Homoallylic alcohol 7 was prepared from (S)-benzyl gly-
cidyl ether7 as described by us earlier.6a Prins cyclization
of 7 with aldehyde 88 using TFA4a resulted in tetrasubsti-
tuted pyran 6, as an only isolable compound, in 55% yield
after hydrolysis of corresponding trifluoroacetate using
Me
Me
NH
OR
O
N
H
OMe OMe
Me
O
O
R = Me, crocacin A (1)
R = H, crocacin B (2)
( )3
Me
Me
Me
Me
NH
OR
NH2
N
O
H
OMe OMe
Me
O
O
O
OMe OMe
Me
O
(+)-crocacin C (3)
R = Me, crocacin D (4)
OH
Me
Me
Me
HO
OH
OBn
+
HO
O
OH
OBn
Me
OMe OMe
7
Me
8
6
5
Scheme 1
SYNLETT 2007, No. 13, pp 2049–2052
1
3
.0
8
.2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-984896; Art ID: D29106ST
© Georg Thieme Verlag Stuttgart · New York

2050
J. S. Yadav et al.
LETTER
K2CO3 in MeOH (Scheme 2). The stereochemistry was revealed the presence of two doublets at d = 4.33 and 4.09
assumed to be in line with that established previously.4–6 ppm (J = 2.2 Hz, geminal coupling) and absence of any
However, this was proved only after elaborating com- characteristic signal regarding rearranged product.
pound 6 to the target molecule, which in all respects was
The substrate 13 was then subjected to ozonolysis to ob-
identical with the reported structure. The primary hydroxy
tain the corresponding acetoxy aldehyde, which, without
group of 6 was selectively protected as TBS ether using
purification was treated with methylene triphenylphos-
phorane to furnish open-chain olefin product 14. Hydro-
lysis of the acetate group in 14 using K2CO3 in MeOH
followed by etherification of resulting secondary alcohol
1.1 equivalents of TBSCl and imidazole while the second-
ary hydroxy group was transformed into methyl ether
using NaH and MeI to produce fully protected 9. De-
benzylation of 9 under Birch conditions provided the cor-
with NaH and MeI in THF afforded methyl ether 15. For
responding primary alcohol, which on protection using
the remaining task of inserting a phenyl group onto the
MOMCl and DIPEA in CH2Cl2 resulted in 10. The TBAF-
olefin function in an anti fashion, we explored two differ-
mediated cleavage of silyl ether 10 followed by treatment
ent methods. First, we opted for cross-metathesis with
of the resulting alcohol with TPP, I2, and imidazole in
styrene using Grubbs II catalyst10 to obtain 16 in 92%
benzene yielded iodo compound 11. Elimination of HI9
yield. Alternatively, we tested Heck coupling11,3k of 15
from 11 using NaH in DMF produced enolic exo-olefin 12
that, on column chromatography, revealed rearranged
product 13.
with iodobenzene using Pd(OAc)2, PPh3, and Et3N in
DMF to obtain 16 in 68% yield. Deprotection of the
MOM ether group in 16 using TFA in CH2Cl2 furnished
We anticipated rearranging the exo-olefin 12 to the more alcohol 5 which in all respects was identical with the re-
stable endo-olefin 13 in an acidic medium but rearrange- ported data.12 Oxidation of alcohol 5 with Dess–Martin
ment occurred on silica gel during flash chromatography. reagent yielded the corresponding aldehyde which was
To confirm that the elimination reaction itself did not immediately added to a mixture of 1713 and NaHMDS in
result in rearranged product, we analyzed the 1H NMR of THF at –78 °C (modified Julia olefination) to obtain
the crude product of elimination reaction which clearly trienoate 18 in 50% yield in two steps. Analytical data for
OMe
OH
OBn
a) TBSCl, imid, CH2Cl2
0 °C to r.t., 6 h, 86%
O
8
Me
TBSO
OH
b) NaH, MeI, THF
0 °C to r.t., 6 h, 90%
HO
O
OBn
TFA, CH2Cl2, then
K2CO3, MeOH
r.t., 5 h, 55%
O
OBn
OH
9
7
6
OMe
OMe
O
a) Na, liq. NH3, THF
10 min, –33 °C, 88%
a) TBAF, THF
r.t., 4 h, 94%
b) MOMCl, DIPEA
CH2Cl2, r.t., 6 h, 94%
I
TBSO
b) TPP, I2, imid
benzene, r.t., 2 h, 95%
O
OMOM
OMOM
11
10
OMe
OMe
O3, TPP, CH2Cl2
then TPPCH2, THF
rearrangement
on silica gel
NaH, DMF
r.t., 12 h
–78 °C to 0 °C, 74%
83%
O
OMOM
O
OMOM
12
13
styrene, Grubbs II cat.
benzene, 50 °C, 12 h, 92%
OMe OAc
a) K2CO3, MeOH
r.t., 2 h, 96%
OMe OMe
OMOM
PhI, Pd(OAc)2, TPP, Et3N
DMF, 100 °C, 8 h, 65%
OMOM
b) NaH, MeI, THF
0 °C to r.t., 6 h, 90%
14
15
a) Dess–Martin reagent OR
CH2Cl2, r.t. 2 h, 88%
OMe OMe
OMe OMe
TFA–CH2Cl2 (3:1), r.t.
Ph
OH
b) LiHMDS, –78 °C
then 17, –78 °C, 1 h, 56%
6 h, 90%
Ph
Ph
OMOM
5
16
O
ref. 3
2 steps
OMe OMe
O
O
O
N
S
3
S
OEt
OEt
17
18
Scheme 2
Synlett 2007, No. 13, 2049–2052 © Thieme Stuttgart · New York

LETTER
Stereoselective Formal Synthesis of Crocacin C
2051
(6) (a) Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron
Lett. 2005, 46, 2133. (b) Yadav, J. S.; Reddy, M. S.; Rao, P.
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Lett. 2006, 47, 4937. (d) Yadav, J. S.; Reddy, M. S.; Prasad,
A. R. Tetrahedron Lett. 2006, 47, 4995.
substrate 18 were in good agreement with those of the
reported compound.12
In conclusion, we successfully achieved the formal syn-
thesis of crocacin C via Prins cyclization and showed that
the Prins cyclization can be used as a powerful tool to
achieve a complex stereochemical outcome. Extension of
Prins cyclization mediated methodology to the synthesis
of several targets is in progress.
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Acknowledgment
M.S.R. thanks CSIR, New Delhi for the award of a fellowship.
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(12) Selected Physical Data. Compound 9: clear oil; Rf = 0.5
(EtOAc–hexane, 1:9). IR (KBr): nmax = 2828, 2856, 1643,
1458, 1092, 838, 697 cm–1. 1H NMR (300 MHz, CDCl3):
d = 7.37–7.17 (m, 5 H), 4.47 (d, 1 H, J = 12.0 Hz), 4.42 (d,
1 H, J = 12.0 Hz), 3.57 (dd, 1 H, J = 10.5, 5.2 Hz), 3.50–3.42
(m, 2 H), 3.33–3.23 (m, 5 H), 3.16 (dd, 1 H, J = 9.8, 1.5 Hz),
2.87 (dt, 1 H, J = 10.5, 4.5 Hz), 2.14–1.98 (m, 2 H), 1.50–
1.38 (m, 1 H), 1.10–1.02 (m, 1 H), 0.88 (d, 3 H, J = 6.4 Hz),
(3) (a) Feutrill, J. T.; Lilly, M. J.; Rizzacasa, M. A. Org. Lett.
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Worthington, P. A.; Williams, J. Chimia 2003, 57, 685.
(h) Dias, L. C.; Oleveira, L. G.; Vilcachagua, J. D.; Florian,
N. J. Org. Chem. 2005, 70, 2225. (i) Chakraborty, T. K.;
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0.84 (s, 9 H), 0.81 (d, 3 H, J = 6.7 Hz), 0.03 (s, 6 H). 13
C
NMR (75 MHz, CDCl3): d = 138.8, 128.2, 127.4, 127.3,
82.5, 79.9, 75.9, 73.5, 72.9, 66.4, 56.0, 38.4, 34.2, 33.0, 25.8,
18.2, 12.1, 9.6, –5.2, –5.3. LSI-MS: m/z = 445 [M+ + Na],
423 [M+ + H].
Compound 13: white solid; mp 158–160 °C; Rf = 0.6
(EtOAc–hexane, 1:9). IR (KBr): nmax = 2969, 2928, 2880,
1678, 1433, 1099, 712 cm–1. 1H NMR (300 MHz, CDCl3):
d = 4.60–4.54 (m, 3 H), 3.72 (dd, 1 H, J = 10.1, 3.1 Hz), 3.57
(t, 1 H, J = 8.5 Hz), 3.44 (dt, 1 H, J = 8.5, 2.3 Hz), 3.40–3.29
(m, 4 H), 3.28 (s, 3 H), 2.12–2.02 (m, 1 H), 1.80–1.68 (m, 1
H), 1.72 (s, 3 H), 0.94 (d, 3 H, J = 7.0 Hz), 0.90 (d, 3 H,
J = 7.0 Hz). 13C NMR (75 MHz, CDCl3): d = 153.2, 96.4,
95.9, 78.9, 78.3, 70.0, 55.1, 54.9, 33.8, 33.7, 19.6, 13.7, 9.5.
LSI-MS: m/z = 267 [M+ + Na].
(l) Raghavan, S.; Reddy, S. R. Tetrahedron Lett. 2004, 45,
5593.
(4) See, for example, (a) Barry, C. S. J.; Crosby, St. R.; Harding,
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Reddy, B. V. S.; Sekhar, K. C.; Gunasekar, D. Synthesis
2001, 885. (d) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.;
Niranjan, N. J. Mol. Catal. A: Chem. 2004, 210, 99.
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Prasad, A. R. Eur. J. Org. Chem. 2003, 1779.
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12216. (d) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker,
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2001, 66, 4679. (h) Kopecky, D. J.; Rychnovsky, S. D.
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2425.
20
Compound 5: clear oil; Rf = 0.3 (EtOAc–hexane, 1:3); [a]D
–3.8 (c 1.80, CH2Cl2); IR (film): n max = 3453, 2970, 2931,
2827, 1599, 1454, 1374, 1191, 1090, 971 cm–1. 1H NMR
(400 MHz, CDCl3): d = 7.40 (d, 2 H, J = 7.6 Hz), 7.32 (t, 2
H, J = 6.8 Hz), 7.24 (tt, 1 H, J = 1.5, 7.6 Hz), 6.59 (d, 1 H,
J = 16.0 Hz), 6.21 (dd, 1 H, J = 7.6, 16.0 Hz), 4.07 (dd, 1 H,
J = 1.5, 7.6 Hz), 3.82 (dd, 1 H, J = 3.8, 11.4 Hz), 3.56 (dd, 1
H, J = 11.4, 4.5 Hz), 3.52 (s, 3 H), 3.31 (s, 3 H), 3.29 (dd, 1
H, J = 3.0, 9.9 Hz), 3.01 (br s, 1 H), 1.90–1.85 (m, 2 H), 1.20
(d, 3 H, J = 6.8 Hz), 0.91 (d, 3 H, J = 6.8 Hz). 13C NMR (75
MHz, CDCl3): d = 136.7, 132.1, 129.2, 128.6, 127.6, 126.4,
88.2, 81.1, 64.3, 61.5, 56.3, 42.2, 35.8, 16.1, 10.3. ESI-
HRMS: m/z calcd for C17H26O3Na [M + Na+]: 301.1779;
found: 301.1791.
Compound 18: light yellowish oil; Rf = 0.5 (EtOAc–hexane,
1:9); [a]D20 –6.7 (c 0.2 CHCl3) {Lit.3d [a]D20 –7.91 (c 0.2
CHCl3)}. IR (film): nmax = 2974, 2929, 1710, 1609, 1450,
1367, 1238, 1154, 1092, 1042, 972 cm–1. 1H NMR (300
MHz, CDCl3): d = 7.33 (d, 2 H, J = 7.5 Hz) 7.25 (t, 2 H,
J = 7.5 Hz), 7.20 (tt, 1 H, J = 8.3, 1.5 Hz), 6.55 (d, 1 H,
J = 15.8), 6.10 (m, 2 H), 6.05 (d, 1 H, J = 15.8 Hz), 5.63 (s,
1 H), 4.09 (q, 2 H, J = 6.7 Hz), 4.03 (m, 1 H), 3.51 (s, 3 H),
3.29 (s, 3 H), 3.13 (dd, 1 H, J = 9.8, 2.2 Hz), 2.50 (m, 2 H),
Synlett 2007, No. 13, 2049–2052 © Thieme Stuttgart · New York

2052
J. S. Yadav et al.
LETTER
HRMS: m/z calcd for C24H34O4Na [M + Na+]: 409.2354;
2.26 (d, 3 H, J = 1.5 Hz), 1.50 (m, 1 H) 1.26 (t, 2 H, J = 7.5
Hz), 1.19 (d, 3 H, J = 6.7 Hz), 0.82 (d, 3 H, J = 6.7 Hz). 13
NMR (50 MHz, CDCl3): d = 167.2, 152.5, 140.0, 136.7,
C
found: 409.2356.
(13) Sulfone 17 was prepared from mercaptobenzothiazole in
three steps in 62% overall yield as shown in Scheme 3.
133.9, 132.0, 129.1, 128.5, 127.5, 126.3, 118.0, 86.3, 81.0,
61.4, 59.5, 56.4, 42.6, 40.0, 18.7, 14.3, 13.9, 9.6. ESI-
a) chloroacetone,
Et3N
b) Ph3P=CHCO2Et,
benzene, reflux
O
N
S
O
O
N
S
SH
S
OEt
c) Oxone,
THF–MeOH–H2O
(4:2:4)
62% (3 steps)
Scheme 3
Synlett 2007, No. 13, 2049–2052 © Thieme Stuttgart · New York

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