Asymmetric synthesis of (+)-passifloricin A and its 6-epimer

Article abstract of DOI:10.1016/j.tetlet.2008.05.070

Stereoselective total syntheses of the antiprotozoal natural product (+)-passifloricin A and its C-6 epimer have been achieved in ～5% overall yield. The strategy is based on Jacobsen epoxidation, Grubbs' metathesis and an Evans' intramolecular oxa-Michael reaction.

Full text of DOI:10.1016/j.tetlet.2008.05.070

Tetrahedron Letters 49 (2008) 4476–4478
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Asymmetric synthesis of (+)-passifloricin A and its 6-epimer
*
S. Chandrasekhar , Ch. Rambabu, A. Syamprasad Reddy
Organic Division-I, Indian Institute of Chemical Technology, 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:
Stereoselective total syntheses of the antiprotozoal natural product (+)-passifloricin A and its C-6 epimer
have been achieved in ꢀ5% overall yield. The strategy is based on Jacobsen epoxidation, Grubbs’ meta-
thesis and an Evans’ intramolecular oxa-Michael reaction.
Received 11 April 2008
Revised 3 May 2008
Accepted 13 May 2008
Available online 16 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Jacobsen epoxidation
Grubbs’ metathesis
Evans’ intramolecular oxa-Michael reaction
Maruoka allylation
The d-lactone ring is an important structural feature of a num-
ber of natural products.1 A few of these natural products also pos-
sess a non-polar lipophilic tail, which gives these compounds
amphiphilic character. Passifloricin A (Fig. 1, 1a) is one such natural
product isolated from Passiflora foetida.2 This compound has shown
interesting antiprotozoal, antifungal properties3 and has attracted
the attention of both analytical and synthetic chemists owing to
the ambiguous assignment of the structure.4 However, Murga et
al. synthesized several isomers of this natural product and
unequivocally assigned the structure as shown in Figure 1.4f
Having a general interest in the total synthesis of bioactive
compounds and in particular, six-membered oxygen heterocycles,5
we have recently employed the intramolecular oxa-Michael reac-
tion5c–e of Evans et al. and Grubbs’ olefin metathesis5a to construct
oxygen heterocycles. The retrosynthetic analysis of 1a/1b based on
this strategy is shown below in Scheme 1.
Ph
O
RCM
O
O
OH
OH OH
10
O
13
6
8
12
12
2a or 2b
OMOM
OH
1a or 1b
Ph
Evans'oxa-Michael
addition
O
O
COOEt
O
12
12
4
OMOM
3
Jacobsen resolution
Scheme 1. Retrosynthesis of compounds 1a and 1b.
molecular oxa-Michael reaction allowed exclusive syn-installation
of the third asymmetric carbon at C-8. Herein, we report our efforts
on the total synthesis of passifloricin A (1a) and its 6-epimer 1b
(Scheme 2).
Our approach also demonstrates the power of Jacobsen’s asym-
metric epoxidation6 as a tool for generating the first stereogenic
center at C-13 followed by Sharpless asymmetric epoxidation
chemistry to install the next stereogenic carbon at C-10. An intra-
Initially, we investigated the cobalt-based chiral salen complex-
mediated resolution of racemic epoxide 4a, which was obtained in
95% yield from commercially available olefin 5. The racemic epox-
ide 4a was resolved efficiently with Jacobsen’s catalyst A6 and the
chiral oxirane 4 was obtained in high enantiomeric excess7 and
45% yield. The regioselective opening of epoxide 4 with allylmag-
nesium chloride resulted in alcohol 6 in 92% yield. Protection of
the alcohol as MOM ether8 7 was achieved using MOMCl and diiso-
propylethylamine which was followed by cross metathesis9 with
ethyl acrylate in the presence of 2 mol % of Grubbs’ catalyst B
(2nd generation) to realize the conjugated ester 8 in quantitative
yield. Reduction of the ester functionality in 8 was achieved with
DIBAL-H at À15 °C to room temperature to give 9 in 96% isolated
O
O
OH OH
10
1b
O
OH OH
O
13
13
8
6
6
10
8
12
12
OH
OH
1a
Figure 1. Structure of (+)-passifloricin A (1a) and 6-epi-passifloricin A (1b).
* Corresponding author. Tel.: +91 4027193210; fax: +91 4027160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.070

S. Chandrasekhar et al. / Tetrahedron Letters 49 (2008) 4476–4478
4477
m-CPBA, CH2Cl2
A, 0.55 eq, H2O, THF
36 h, 45%, 94% ee
allylmagnesium chloride
12
12
12
O
12
4a
O
0 ºC, 1 h, 95%
dry ether, 0 ºC to rt, 1 h, 92%
OH
5
4
6
MOMCl, iPr2EtN, CH2Cl2
0 ºC to rt, 2 h, 95%
DIBAL-H, CH2Cl2,
Ethyl acrylate, B (2 mol%)
COOEt
12
12
CH2Cl2, reflux, 12 h, 99%
-15 ºC to rt, 3 h, 96%
OMOM
OMOM
7
8
OH OH
Ti(OiPr)4, (+)-DET, tBuOOH, CH2Cl2
4 Å MS, -20 ºC, 8 h, 85%
O
Red-Al, CH2Cl2
OH
OH
12
12
12
0 ºC to rt, 6 h, 90%
OMOM
OMOM
10
OMOM
9
Ph
11
OH
O
O
BAIB, TEMPO, CH2Cl2, rt, 1 h
then Ph3P=CHCOOEt, 80%
PhCHO, KOtBu, THF
0 ºC, 45 min, 72%
DIBAL-H, CH2Cl2
COOEt
COOEt
-78 ºC, 1 h, 90%
12
12
OMOM
OMOM
3
12
Ph
Ph
Ph
O
O
O
O
OH
O
O
OH
Table 1
CHO
12
12
12
OMOM
OMOM
OMOM
13
2a
2b
H
H
N
Mes
Cl
N
N
Mes
H
N
Co
Ru
O
O
Cl
Ph
AcO
PCy3
(S,S)-(salen)CoIII(OAc)
Grubbs' catalyst (2nd generation)
(B)
(A)
Scheme 2. Stereoselective synthesis of compounds 2a and 2b.
yield.10 The stage was then set for introduction of the following
stereogenic hydroxy functionality under Sharpless asymmetric
epoxidation conditions11 using (+)-DET to give chiral epoxy alcohol
10 in 85% isolated yield. The reductive opening of this epoxide was
achieved with Red-Al12 to realize the 1,3-diol 11. This diol 11, on
selective oxidation in the presence of bis(acetoxy)iodoben-
zene (BAIB) and 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO),
followed by exposure of the crude b-hydroxy aldehyde to ethoxy-
carbonylmethylene triphenylphosphorane furnished d-hydroxy-
rate the diastereomers 2a and 2b, which were converted indepen-
dently into (+)-passifloricin A (1a) (Scheme 3) and its 6-epimer 1b
(Scheme 3a), respectively.
Diastereomer 2a was subjected to acrylation with acrolyl chlo-
ride in the presence of diisopropylethylamine to generate the diene
ester 14a setting the stage for the Grubbs’ ring-closing metathesis
Ph
O
a
,b-unsaturated ester 12 in 80% overall yield for the two steps.13
acrolyl chloride, iPr2NEt
O
O
O
C (5 mol%), CH2Cl2
This substrate has all the functionalities necessary to perform the
tethered Evans’ intramolecular oxa-Michael syn addition reaction14
which was executed easily using benzaldehyde and potassium tert-
butoxide at 0 °C in anhydrous THF to furnish benzylidene acetal 3
in 72% isolated yield. The diastereoselectivity was greater than 95%
favoring the more stable syn-isomer. The ester group in 3 was re-
duced to aldehyde15 13, which on allylation gave a diastereomeric
mixture of 2a and 2b in variable yields and ratios (Table 1).16 The
chiral BINOL-mediated Maruoka allylation17,5a,e (Table 1, entry 4)
was most efficient providing a syn-selectivity of 90% albeit with a
low yield of product. Column chromatography allowed us to sepa-
2a
reflux, 6 h, 92%
CH2Cl2, 0 ºC to rt, 1 h, 96%
12
OMOM
14a
Ph
O
O
O
O
HCl (4N), THF
rt, 12 h, 89%
1a
12
OMOM
15a
Scheme 3. Stereoselective synthesis of 1a.
Ph
O
Table 1
acrolyl chloride, iPr2NEt
O
O
O
C (5 mol%), CH2Cl2
Metal catalyzed allylation of aldehyde 13
2b
reflux, 6 h, 92%
Entry
Reagents and conditions
Yielda (%)
syn:antib
CH2Cl2, 0 ºC to rt, 1 h, 96%
12
OMOM
14b
1
2
3
4
Allyl bromide, Mg, dry ether, 0 °C, 1 h
Allyl bromide, Zn, THF/satd NH4Cl, À15 °C, 1 h
Allyl bromide, In, THF/H2O, À15 °C, 1 h
Allyltri-n-butyltin, Ti(OiPr)4, TiCl4, Ag2O,
(R)-BINOL, CH2Cl2, 24 h
92
98
95
45
55:45
24:76
32:68
90:10
Ph
O
O
O
O
HCl (4N), THF
rt, 12 h, 89%
1b
12
a
OMOM
Isolated yield after column chromatography purification.
15b
b
Ratio based on the yields of both isomers after separation by silica gel
chromatography.
Scheme 3a. Stereoselective synthesis of 1b.

4478
S. Chandrasekhar et al. / Tetrahedron Letters 49 (2008) 4476–4478
(RCM)18 reaction. The diene ester 14a in CH2Cl2 underwent a
smooth intramolecular metathesis reaction in the presence of
5 mol % of Grubbs’ catalyst C (1st generation) to produce the a,b-
unsaturated lactone 15a in 92% yield. Treatment of lactone 15a
with 4 N HCl in THF resulted in cleavage of the MOM-ether and
benzylidene acetal to afford passifloricin A (1a) in 89% yield.19
The other diastereomer 2b was also subjected to the same
sequence of reactions to realize the 6-epimer 1b. The spectroscopic
data of both compounds 1a and 1b were in full agreement with
those reported in the literature.4f
Chandrasekhar, S.; Rambabu, Ch.; Shyamsunder, T. Tetrahedron Lett. 2007, 47,
4683.
6. (a) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 6776; (b)
Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A.
E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307.
7. The enantioselectivity of compound
4 has been determined as 94% ee
using chiral HPLC by conversion of 4-nitrobenzoate ester of compound 6.
i
{Chiralcel OD-H, PrOH/hexane (1:99), flow rate 0.4 ml/min, tR = 11.30 (major),
tR = 13.21 (minor)}: Chen, J.; Li, Y.; Cao, X. P. Tetrahedron: Asymmetry 2006, 17,
933.
8. Stork, G.; Takahashi, J. J. Am. Chem. Soc. 1977, 99, 1275.
9. (a) Grubbs, R. H. Handbook of Olefin Metathesis; VCH-Wiley: Wienheim, 2003;
(b) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc.
2000, 122, 3783; (c) Choi, T. L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int.
Ed. 2001, 40, 1277.
10. Fukuda, T.; Shindo, M.; Shishido, K. Org. Lett. 2003, 5, 749.
11. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974; (b) Gao, Y.;
Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am.
Chem. Soc. 1987, 109, 5765.
12. (a) Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 53, 4081; (b) Vitli, S. M.
Tetrahedron Lett. 1982, 23, 4541; (c) Trace contamination of the 1,2-diol was
eliminated by exposing the crude reaction mixture to NaIO4 followed by
chromatography.
PCy3
H
Cl
Cl
Ru
Ph
PCy3
Grubbs' Catalyst (1st generation)
13. Varele, J. M. Tetrahedron Lett. 2006, 47, 715.
14. Evans, D. A.; Gouchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446.
15. Zhu, B.; Panek, J. S. Org. Lett. 2000, 2, 2575.
(C)
16. (a) Petrier, C.; Luche, J. L. J. Org. Chem. 1985, 50, 910; (b) Einhorn, C.; Luche, J. L.
J. Organomet. Chem. 1987, 322, 177; (c) Chattopadhyay, A. J. Org. Chem. 1996, 61,
6104.
17. Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708.
18. (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446; (b)
Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012; (c) Trnka, T. M.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18.
In conclusion, asymmetric total syntheses of (+)-passifloricin A
and its 6-epimer have been achieved using Jacobsen’s epoxidation,
Grubbs’ metathesis, an Evans’ intramolecular oxa-Michael and a
Maruoka allylation as key steps.20
Acknowledgment
19. Lemos, E.; Poree, F. H.; Commercon, A.; Betzer, J. F.; Pancrazi, A.; Ardisson, J.
Angew. Chem., Int. Ed. 2007, 46, 1917.
20. Spectral data of selected compounds: (2S)-2-Tetradecyloxirane (4): [
1.0, CHCl3); IR (KBr): mmax 2925, 2854, 1462, 1023 cmÀ1 1H NMR (300 MHz,
CDCl3): d 2.86–2.80 (m, 1H); 2.68 (dd, J = 5.2, 3.7 Hz, 1H); 2.40 (dd, J = 5.2,
2.2 Hz, 1H); 1.54–1.41 (m, 2H); 1.36–1.22 (m, 24H); 0.88 (t, J = 6.7 Hz, 3H); 13
a] +0.6 (c
D
C.R. and A.S.P. thank CSIR-New Delhi for the award of research
fellowships.
;
C
NMR (75 MHz, CDCl3): d 52.3, 47.0, 32.5, 31.9, 29.7, 29.6 (several overlapped
References and notes
peaks), 29.4, 25.9, 22.7, 14.1; MS (LC): m/z 241.2 (M+H)+; HRMS calcd for
C
16H32ONa (M+Na)+: 263.2345; found, 263.2350.
1. (a) Negishi, E.; Kotora, M. Tetrahedron 1997, 53, 6707; (b) Collins, I. J. Chem. Soc.,
Perkin Trans. 1 1999, 1377; (c) Carter, N. B.; Nadany, A. E.; Sweeney, J. B. J. Chem.
Soc., Perkin Trans. 1 2002, 2324; (d) Hoffmann, H. M. R.; Rabe, J. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 94.
2. Echeverri, F.; Arango, V.; Quinones, W.; Torres, F.; Escobar, G.; Rosero, Y.;
Archbold, R. Phytochemistry 2001, 56, 881.
3. Cardona, W.; Quinones, W.; Echeverri, F. Molecules 2004, 9, 666.
4. Syntheses of regioisomers: (a) Murga, J.; Garcia-Fortanet, J.; Carda, M.; Marco, J.
A. Tetrahedron Lett. 2003, 44, 7909; (b) Garcia-Fortanet, J.; Murga, J.; Carda, M.;
Marco, J. A. Org. Lett. 2003, 5, 1447; (c) Cossy, J.; BouzBouz, S.; Popkin, M. C.R.
Chimie 2003, 6, 547; (d) BouzBouz, S.; Cossy, J. Tetrahedron Lett. 2003, 44, 4471;
13C NMR spectroscopic analysis: (e) Bifulco, G.; Gomez-Paloma, L.; Riccio, R.
Tetrahedron Lett. 2003, 44, 7137; Synthesis of passifloricin: (f) Murga, J.; Garcia-
Fortanet, J.; Carda, M.; Marco, J. A. J. Org. Chem. 2004, 69, 7277; (g) Curran, D. P.;
Moura-Letts, G.; Pohlman, M. Angew. Chem., Int. Ed. 2006, 45, 2423.
5. (a) Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S. Tetrahedron Lett. 2004, 45,
9299; (b) Chandrasekhar, S.; Prakash, S. J.; Shyamsunder, T. Tetrahedron Lett.
2005, 46, 6651; (c) Chandrasekhar, S.; Shyamsunder, T.; Prakash, S. J.;
Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett. 2006, 47, 47; (d) Chandrasekhar,
S.; Rambabu, Ch.; Prakash, S. J. Tetrahedron Lett. 2006, 47, 1213; (e)
Ethyl (2E,6S)-6-(methoxymethyl)-2-icosenoate (8): [
a] +8.7 (c 1.0, CHCl3); IR
D
(KBr): mmax 2925, 2853, 1723, 1039 cmÀ1 1H NMR (200 MHz, CDCl3): d 6.93–
;
6.78 (m, 1H); 5.72 (d, J = 15.6 Hz, 1H); 4.55–4.47 (m, 2H); 4.08 (q, J = 7.0 Hz,
2H); 3.49–3.37 (m, 1H); 3.26 (s, 3H); 2.25–2.12 (m, 2H); 1.60–1.14 (m, 31H);
0.80 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 166.5, 148.8, 121.4, 95.5,
76.9, 60.0, 55.5, 34.2, 32.6, 31.8, 29.7, 29.6 (several overlapped peaks), 27.9,
25.1, 22.6, 14.2, 14.0; MS (LC): m/z 421.2 (M+Na)+; HRMS calcd for C24H46O4Na
(M+Na)+: 421.3293; found, 421.3282.
Ethyl
oxan-4-yl}acetate (3): [
1738, 1459, 1031, 740 cmÀ1
2-{(2S,4R,6R)-6-[(3S)-3-(methoxymethoxy)heptadecyl]-2-phenyl-1,3-di-
a]
D
+4.5 (c 1.0, CHCl3); IR (KBr): mmax 2926, 2853,
;
1H NMR (300 MHz, CDCl3): d 7.46–7.43 (m, 2H);
7.35–7.27 (m, 3H); 5.52 (s, 1H); 4.61 (s, 2H); 4.31–4.20 (m, 1H); 4.15 (q,
J = 7.5 Hz, 2H); 3.85–3.77 (m, 1H); 3.58–3.49 (m, 1H); 3.35 (m, 3H); 2.70
(dd, J = 15.4, 6.7 Hz, 1H); 2.42 (dd, J = 15.4, 6.4 Hz, 1H); 1.74–1.19 (m,
35H); 0.89 (t, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 170.6, 138.4,
128.4, 128.0, 125.9, 100.4, 95.3. 77.2, 76.7, 73.1, 60.4, 55.4, 40.9, 36.5, 34.3,
31.8,31.6, 29.7, 29.6 (several overlapped peaks), 29.2, 25.1, 22.6, 14.1, 14.0; MS
(LC): m/z 571.4 (M+Na)+; HRMS calcd for C33H56O6Na (M+Na)+: 571.3974;
found,571.3969.