Total synthesis of hyptolide

Article abstract of DOI:10.1016/j.tetlet.2008.07.033

The total synthesis of hyptolide, a naturally occurring α,β-unsaturated six-membered δ-lactone substituted with a polyoxygenated chain, is described. Sharpless kinetic resolution and opening of two different epoxy alcohols under two different conditions-Swern oxidation conditions and a radical reaction using Cp₂TiCl-fixed the stereocenters at C-9, C-11, and C-12, respectively. Brown's asymmetric allylation reaction installed the remaining stereocenter at C-6. A RCM protocol was used for construction of the α,β-unsaturated six-membered δ-lactone moiety of the molecule.

Full text of DOI:10.1016/j.tetlet.2008.07.033

Tetrahedron Letters 49 (2008) 5502–5504
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Total synthesis of hyptolide
*
Tushar Kanti Chakraborty , Subhas Purkait
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:
The total synthesis of hyptolide, a naturally occurring
a,b-unsaturated six-membered d-lactone substi-
Received 6 June 2008
Revised 3 July 2008
Accepted 5 July 2008
Available online 9 July 2008
tuted with a polyoxygenated chain, is described. Sharpless kinetic resolution and opening of two different
epoxy alcohols under two different conditions—Swern oxidation conditions and a radical reaction using
Cp2TiCl—fixed the stereocenters at C-9, C-11, and C-12, respectively. Brown’s asymmetric allylation reac-
tion installed the remaining stereocenter at C-6. A RCM protocol was used for construction of the
a,b-
unsaturated six-membered d-lactone moiety of the molecule.
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Hyptolide
Radical epoxide opening
Ring-closing metathesis
In recent years, naturally occurring six-membered
a,b-unsatu-
OAc OAc
OAc OAc
rated d-lactones substituted with a polyoxygenated chain have
attracted considerable attention from synthetic as well as
bioorganic chemists, because of their interesting structures and
important biological activities.1,2 Representative examples of this
class of molecules are hyptolide (1),3 spicigerolide (2),4 anamarine
(3)5 and synrotolide (4)6 (Fig. 1).
These compounds were isolated from species of Hyptis, Syncol-
ostemon, and related genera of the family Lamiaceae, and show
interesting pharmacological properties.3–6 As a result, many syn-
thetic approaches have been reported for their syntheses, where
mostly carbohydrates were used as chiral pool starting materials.7
Recently, we developed an efficient methodology by which a
chiral 4-hydroxy-2,3-unsaturated carbonyl compound C (Scheme
1) could be obtained via opening of a 3,4-epoxy alcohol A under
Swern oxidation conditions.8 We have also demonstrated another
method for the synthesis of chiral 1,3-diols,9 such as D, via a radi-
cal-mediated opening of a 2,3-epoxy alcohol B using Cp2TiCl10 as
shown in Scheme 1. In this Letter, we report the total synthesis
of hyptolide (1)11 to demonstrate the practical utilities of these
two methodologies developed by us (see Scheme 2).
O
O
O
O
OAc OAc
OAc
1
2
OAc OAc
OH OAc
O
O
O
O
OAc OAc
OAc OH
4
3
Figure 1.
resultant primary alcohol as a TBDPS-ether furnished compound 8
in 81% yield in two steps. Stereoselective epoxidation of 8 with
mCPBA afforded the epoxide 9 (90%, 2:1 in favor of the required
isomer). The stage was now set to carry out the crucial radical-
mediated epoxide opening from the hydroxy side to give the req-
uisite 1,3-diol. Accordingly, when compound 9 was treated with
Cp2TiCl, generated in situ from Cp2TiCl2 and Zn dust,9,10 diol 10
was obtained in 85% yield. Acetonide protection of the 1,3-diol of
10 gave 11. The 13C NMR spectrum of 11 showed the chemical
shifts of the methyl carbons of the acetonide function at 19.82
and 29.9 ppm and that of the ketal carbon at 98.28 ppm, thereby
confirming it to be a ‘1,3-syn’ acetonide.14 This, in turn, proved that
the major epoxide obtained during the mCPBA epoxidation of 8
was indeed the syn-epoxy alcohol 9. Chemoselective deprotection
of the TBDPS-ether using TBAF in THF afforded the primary alcohol
11a, which was converted to alkene 12 in two steps. Oxidation of
11a was followed by selective Z-olefination following Still’s proto-
col,15 using the ketophosphonate (CF3CH2O)2P(O)CH2CO2Me, to
give 12 as the major product in a Z:E ratio of 95:5. The minor
Our synthesis started from compound 6, which was prepared
from alcohol 5 according to the reported procedure8 involving
Sharpless asymmetric kinetic resolution,12 followed by protective
group manipulations. With chiral epoxy alcohol 6 in hand, it was
subjected to oxidation under Swern conditions13 to afford exclu-
sively the trans enal, (4R,5S,E)-5-(tert-butyl-dimethylsilyloxy)-4-
hydroxy-hex-2-en-1-al (7) in 90% yield. Reduction of the aldehyde
functionality with DIBAL-H followed by selective protection of the
* Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193108.
E-mail address: chakraborty@iict.res.in (T. K. Chakraborty).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.033

T. K. Chakraborty, S. Purkait / Tetrahedron Letters 49 (2008) 5502–5504
5503
OH
Swern oxidation
Cp2 TiCl
O
R
OP'
R
R
OP'
CHO
OP
OP
OP OH
A: P= protecting group and P' = H
C
D
B: P = Hand P' = protecting group
Scheme 1.
O
OH
i
OH
ii
OPMB
CHO
(ref.8)
(ref.8)
OTBS
OH
6
5
7
OTBS
OH
OH
v
iii, iv
vi
OTBDPS
OTBDPS
O
OTBS
OTBS
8
9
(
syn
:anti = 2:1)
O
O
OH OH
O
O
vii
ix
COOMe
OR
OTBDPS
OTBS
OTBS
x
OTBS
12
10
11: R = TBDPS
11a: R = H
viii
O
O
O
O
xi
xii
CHO
OH
OTBS
OTBS
O
14
13
O
xiv
O
O
xiii
1
O
O
O
O
OTBS
OTBS
15
16
Scheme 2. Reagents and conditions: (i) Ref. 88; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 1 h, 90%; (iii) DIBAL-H, CH2Cl2, ꢀ78 °C, 0.5 h; (iv) TBDPSCl, Et3N, DMAP (cat), CH2Cl2,
0 °C to rt, 3 h, 81% over two steps; (v) mCPBA, CH2Cl2, 0 °C, 12 h, 90% (2:1 in favor of the required isomer); (vi) Cp2TiCl2, Zn, ZnCl2, THF, ꢀ20 °C to rt, 12 h, 85%; (vii) 2,2-
dimethoxypropane, CSA (cat), CH2Cl2, rt, 1 h; (viii) TBAF, THF, 0 °C to rt, 1 h, 85%, over two steps; (ix) (a) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 2 h; (b)
(CF3CH2O)2P(O)CH2CO2Me, NaH, THF, ꢀ78 °C to 0 °C, 1.5 h, 80% (Z:E = 95:5) over two steps; (x) (a) step iii; (b) DMP, CH2Cl2, 0 °C to rt, 0.5 h, 85% over two steps; (xi) (+)-
Ipc2B(allyl), Et2O, ꢀ78 °C, 1 h, 70%; (xii) acryloyl chloride, Et3N, DMAP, CH2Cl2, 0 °C; 15 min, 70%; (xiii) Grubbs’ 1st generation catalyst, CH2Cl2, 42 °C, 5 h, 85%; (xiv) (a) PPTS,
MeOH, rt, 24 h; (b) Ac2O, Et3N, DMAP (cat), CH2Cl2, 0 °C to rt, 0.5 h, 80% over two steps.
isomer could be removed chromatographically after the reduction
step. The ,b-unsaturated aldehyde 13 was obtained from 12 in
References and notes
a
1. (a) Davis-Coleman, M. T.; Rivett, D. E. A. Naturally Occurring 6-Substituted 5,6-
two steps. DIBAL-H reduction of 12 afforded the corresponding pri-
mary alcohol, which on oxidation with Dess Martin periodinane
(DMP)16 furnished aldehyde 13. Asymmetric allylation of 13 using
Brown’s protocol17 afforded the secondary alcohol 14 as the only
diastereomer as determined by 1H NMR. Alcohol 14 on acylation
with acryloyl chloride afforded bis-olefinic compound 15 in 49%
yield over the two steps.
Dihydro-a-pyrones. In Progress in the Chemistry of Organic Natural Products;
Herz, W., Grisebach, H., Kirby, G. W., Tamm, Ch., Eds.; Springer: New York,
1989; Vol. 55, pp 1–35; (b) Collett, L. A.; Davies-Coleman, M. T.; Rivett, D. E. A.
Naturally Occurring 6-Substituted 5,6-Dihydro-a-pyrones. In Progress in the
Chemistry of Organic Natural Products; Herz, W., Falk, H., Kirby, G. W., Moore, R.
E., Tamm, Ch., Eds.; Springer: New York, 1998; Vol. 75, pp 182–209; (c) Pereda-
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Plenum: New York, 1995; pp 83–112.
Ring-closing metathesis (RCM) of 15 using Grubbs’ 1st genera-
2. (a) Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garcia-Rojas, C. M.
Tetrahedron 2001, 57, 47–53; (b) Pereda-Miranda, R.; Hernandez, L.;
Villavicencio, M. J.; Novelo, M.; Ibarra, P.; Chai, H.; Pezzuto, J. M. J. Nat. Prod.
1993, 56, 583–593.
tion catalyst18 furnished the
a,b-unsaturated d-lactone 16 in 85%
yield, which was converted to hyptolide 1 in two steps—global
deprotection followed by acetylation of the resulting triol to afford
1 in 80% yield. The spectral and analytical data of 119 were in good
agreement with those reported in the literature.
In conclusion, we have shown the utility of 2,3-epoxide opening
reactions under two different conditions for the total synthesis of
hyptolide. Further applications of these methodologies to the syn-
thesis of other natural products are in progress, and the results will
be reported in due course.
3. (a) Birch, A. J.; Butler, D. N. J. Chem. Soc. 1964, 4167–4168; (b) Achmad, S. A.;
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ꢀr, A.; Makmur, L.; Norrestam, R. Acta Chem. Scand. 1987, 41B,
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2004, 60, 2979–2985; (b) Falomir, E.; Murga, J.; Ruiz, P.; Carda, M.; Marco, J. A. J.
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W.; Lorenz, K.; Ma, W. Tetrahedron Lett. 1987, 28, 47–50; (f) Srihari, P.; Kumar,
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Krishna, P. R.; Reddy, P. S. Tetrahedron 2007, 63, 3995–3999.
´
Acknowledgement
The authors thank CSIR, New Delhi, for a research fellowship
(S.P.).

5504
T. K. Chakraborty, S. Purkait / Tetrahedron Letters 49 (2008) 5502–5504
8. Chakraborty, T. K.; Purkait, S.; Das, S. Tetrahedron 2003, 59, 9127–9135.
9. (a) Chakraborty, T. K.; Dutta, S. J. Chem. Soc., Perkin Trans. 1 1997, 1257–1259;
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Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110, 8561–8562.
11. For previous synthesis of hyptolide see: (a) Murga, J.; García-Fortanet, J.;
Carda, M.; Marco, J. A. Tetrahedron Lett. 2003, 44, 1737–1739; (b) García-
Fortanet, J.; Murga, J.; Carda, M.; Marco, J. A. Tetrahedron 2004, 60, 12261–
12267.
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Am. Chem. Soc. 1987, 109, 5765–5780.
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Swern, D. Tetrahedron Lett. 1981, 35, 2473–2476.
14. (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945–948; (b)
Evans, D. A.; Reiger, D. L.; Gage, J. R. Tetrahedron Lett. 1990, 31, 7099–7100.
15. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
16. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
17. Brown, H. C.; Guang-Ming, H.; Ramachandran, P. V. Tetrahedron Lett. 1997, 38,
2417–2420.
(m, 6H, Ar-H), 3.96 (m, 1H), 3.72 (dd, 1H, J = 9.8, 5.3 Hz), 3.66–3.50 (m, 3H),
1.91 (dt, 1H, J = 12.8, 2.26 Hz), 1.63 (m, 1H), 1.40 (s, 3H), 1.35 (s, 3H), 1.16 (d,
3H, J = 6.0 Hz), 1.05 (s, 9H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3, 75 MHz)
d 135.64, 133.69, 129.54, 127.55, 98.28, 73.61, 71.41, 69.77, 67.55, 30.23, 29.90,
26.81, 25.86, 20.46, 19.82, 18.15, 18.05, ꢀ4.36, ꢀ4.64; MS (ESIMS): m/z: 565
[M+Na]+; (b) Analytical and spectral data of compound 16: ½a 2D7
ꢁ
+13.17 (c 1.05,
CHCl3); IR (neat): mmax 2929, 2857, 1724, 1465, 1380, 1248, 1200, 1150, 1102,
1040 cmꢀ1 1H NMR (300 MHz, CDCl3): d 6.86 (m, 1H), 6.04 (dd, 1H, J = 9.8,
;
1.5 Hz), 5.64–5.61 (m, 2H), 5.39 (ddd, 1H, J = 12.0, 6.8, 5.3 Hz), 4.60 (dq, 1H,
J = 12.0, 7.5 Hz), 3.65–3.52 (m, 2H), 2.48–2.28 (m, 2H), 1.58 (dt, 1H, J = 12.8,
5.2 Hz), 1.42 (s, 3H), 1.36 (s, 3H), 1.35 (m, 1H), 1.13 (d, 3H, J = 6.0 Hz), 0.86 (s,
9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 163.69, 144.53,
134.01, 127.81, 121.57, 98.59, 74.41, 73.27, 71.08, 66.64, 33.01, 30.12, 29.96,
25.79, 20.28, 19.63, 18.02, ꢀ4.39, ꢀ4.67; MS (ESIMS): m/z: 419 [M+Na]+; (c)
Analytical and spectral data of hyptolide (1): ½a D27
ꢁ
+11.2 (c 0.58, CHCl3), reported
+12.1 (c 0.68, CHCl3);11b IR (neat): mmax 2926, 2854, 1728, 1427, 1372, 1226,
1152, 1020 cmꢀ1 1H NMR (500 MHz, CDCl3): d 6.87 (ddd, 1H, J = 9.8, 5.5,
,
3.1 Hz), 6.03 (ddd, 1H, J = 9.8, 2.6, 1 Hz), 5.77 (dd, 1H, J = 10.4, 8.3 Hz), 5.56–
5.50 (m, 2H), 5.28 (ddd, 1H, J = 10.9, 8.8, 4.6 Hz), 4.98 (dq, 1H, J = 9.8, 6.2 Hz),
4.92 (dt, 1H, J = 9.3, 3.1 Hz), 2.49–2.35 (m, 2H),2.07 (s, 3H), 2.03 (s, 3H), 2.02 (s,
3H), 1.97 (m, 1H), 1.83 (m, 1H), 1.20 (d, 3H, J = 6.7 Hz); 13C NMR (CDCl3,
150 MHz) d 170.65, 170.34, 169.76, 163.46, 144.65, 131.32, 130.71, 121.48,
73.79, 70.90, 70.45, 66.48, 34.73, 29.47, 21.12, 21.10, 21.06,14.69; MS (ESIMS):
m/z: 391 [M+Na]+; HRMS (ESI) calcd for C18H24O8Na [M+Na]+ 391.1368. Found
391.1362.
18. (a) Gradillas, A.; Pérez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086–6101;
(b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238; (c) Grubbs, R. H.
Tetrahedron 2004, 60, 7117–7140; (d) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18–19; (e) Fürstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043.
19. (a) Analytical and spectral data of compound 11: ½a D27
ꢁ
+3.09 (c 1.06, CHCl3); IR
(neat): mmax 3069, 2931, 2860, 1742, 1592, 1466, 1430, 1378, 1254, 1201,
1110 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.72–7.65 (m, 4H, Ar-H), 7.45–7.33
;