A convergent route to β-hydroxy δ-lactones through Prins cyclisation as the key step: Synthesis of (+)-prelactones B, C and V

Article abstract of DOI:10.1016/j.tetlet.2005.01.121

Reactions of homoallylic alcohols with aldehydes in the presence of acid catalysts gave multisubstituted tetrahydropyrans with the creation of one to three new stereogenic centres in a single-pot process. The utility of this approach is extended to the en

Full text of DOI:10.1016/j.tetlet.2005.01.121

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2133–2136
A convergent route to b-hydroxy d-lactones through Prins
cyclisation as the key step: synthesis of (+)-prelactones B, C and Vq
J. S. Yadav,* M. Sridhar Reddy and A. R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received 27 October 2004; revised 10 January 2005; accepted 21 January 2005
Dedicated to Dr. A. V. Rama Rao on the occasion of his 70th birthday
Abstract—Reactions of homoallylic alcohols with aldehydes in the presence of acid catalysts gave multisubstituted tetrahydropyrans
with the creation of one to three new stereogenic centres in a single-pot process. The utility of this approach is extended to the enan-
tioselective syntheses of (+)-prelactones B, C and V.
Ó 2005 Elsevier Ltd. All rights reserved.
A strategy that has been gaining importance for the ste-
reoselective synthesis of tetrahydropyrans (THPs) is the
acid-promoted Prins-type reaction involving cyclisation
of an oxycarbenium ion generated in situ either from
reaction of the parent homoallylic alcohol1 with an alde-
hyde or from a homoallylic acetal2 or a-acetoxy ester.3
Such reactions have been widely used for the construc-
tion of tetrahydropyrans with different functionalities
like hydroxyl,1a,c,d acetoxy,2d,4 acylamino5 or a halo-
gen1a,b,e,4a at C-4 by judicious choice of reaction condi-
tions. This strategy has the advantage of being very
flexible; by correct choice of the appropriate aldehyde
and the substitution pattern in the homoallylic alcohol,
a range of functionalised side-chains with complex sub-
stitution patterns can be installed on the THP ring in a
single-pot process (Scheme 1).1a,b,6 This type of cyclisa-
tion has been successfully used in the synthesis of some
natural products.6,4b In this report, we extend the use of
this method for the synthesis of triketide d-lactones.
Nu
O
R2
R1
R3
+
R3
R4
R2
R1
acid catalyst
Nu
R4CHO
R4CHO
OH
OH
predominant isomer
Nu
R2
R1
R3
R4
R2
R1
acid catalyst
Nu
+
R3
O
major isomer
Scheme 1.
chiral d-lactones isolated from various polyketide mac-
rolide producing microorganisms.7 The discovery of
these molecules supports the widely accepted hypothesis
of step-by-step functionalisation of growing polyketide
chains in the biosynthesis of macrolides.8 They represent
important structural moieties in a large number of
bioactive natural products such as mevinolin and
compactin, inhibitors of cholesterol biosynthesis,9a
phomolactone9b and asperlin,9c antibiotics and massoi-
alactone,9d tetrahydro 6-(1-hydroxyundecyl)-2H-pyran-
2-one,9e attractant or defence substances for animals
and insects. Hence, there has been increasing attention
paid to the synthesis of d-lactones.10–12 The general
strategy that we describe here for the synthesis of these
prelactones, will allow the preparation of material
for use as standards during mechanistic studies of
d-Lactones are of great importance, being structural
components of a large number of organic natural prod-
ucts and serving as intermediates in the syntheses of sev-
eral drugs and natural products. Prelactones 1–5 (Fig. 1)
constitute an important group of highly functionalised
Keywords: Prins cyclisation; d-Lactones; Homoallylic alcohol;
Tetrahydropyrans.
q IICT Communication no. 050205.
*
Corresponding author. Tel.: +91 40 27193030; fax: +91 40
27160512; e-mail: yadav@iict.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.121

2134
J. S. Yadav et al. / Tetrahedron Letters 46 (2005) 2133–2136
OH
OH
OH
OH
O
Me
O
Me
R
Me
Me
O
O
O
O
O
O
1 (prelactone B)
5
3 (prelactone V, R = Me)
4 (prelactone E, R = Et)
2 (prelactone C)
Figure 1.
i
ii
iii
85% (overall)
BnO
BnO
O
88%
86%
OH
OH
OH
6
7
8
OH
OBn
9
OH
OMOM
OMOM
iv
vi
v
BnO
BnO
HO
RCHO (4 eq)
quant
R
quant
O
O
R
O
R
10a, b, c
11a, b, c
12a, b, c
OMOM
a, R=i-Pr
b, R=trans-propenyl
c, R=Me
vii
viii
1, 2 and 3
85-90%
82-86%
O
O
R
13a, b, c
Scheme 2. Reagents and conditions: (i) CH3C„CLi, BF3ÆOEt2, THF, ꢀ78 °C, 2 h; (ii) Na, NH3 liq, THF, 5 h; (iii) BnBr, NaH, DMF, 0 °C–rt, 6 h;
(iv) (a) amberlyst-15 (1 g for 5 mmol of 2), DCM, reflux, 5–6 h, 48–55% or (b) TFA (30 equiv w.r.t. HAA to 9), 0 °C, 3 h then K2CO3, MeOH, rt, 1 h,
60–68% or (c) BF3ÆOEt2, AcOH, 0 °C, 2–3 h then K2CO3, MeOH, rt, 1 h, 52–60%; (v) (iPr)2NEt, MOMCl, DMAP, DCM, 0 °C–rt, 12 h (vi) Li, NH3
liq, 2 min; (vii) PCC (4 equiv), benzene, reflux, 4–5 h; (viii) 1 N HCl, THF, 0 °C–rt, 6 h.
polyketide biosynthesis and will provide a flexible route
for the synthesis of di-, tri- and tetra-substituted d-lac-
tones in a highly stereocontrolled manner.
cyclisations with TFA1a or BF3ÆOEt2 in AcOH4b affor-
ded, after hydrolysis of the esters with potassium car-
bonate in MeOH, tetrahydropyrans 10a–c in 60–68%
and 52–60% yields, respectively, with the complete dis-
appearance of 9. The predominant isomers were isolated
by flash column chromatography and were found to
have all substituents in equatorial positions. The stereo-
In the synthesis (Scheme 2), the key intermediate, homo-
allylic alcohol 9, was prepared from (+)-benzyl glycidyl
ether 6.13 Opening of the epoxide in benzyl glycidyl ether
6 with propynyllithium in the presence of BF3ÆOEt2 re-
sulted in homopropargyl alcohol 7 in 88% yield. Birch
reduction of 7 furnished dihydroxy trans olefin 8 in
86% yield. Selective protection of the primary hydroxyl
group as a benzyl ether in the presence of NaH in
DMF afforded 9 in 65% yield along with 20% of the
di-O-benzyl protected material and 8% of starting mate-
rial. The doubly protected compound could be con-
verted back to diol 8 with lithium in liquid ammonia
allowing repetition of the protection proceeded to give
9 was in 85% overall yield.
1
chemistry was assigned on the basis of H NMR coup-
ling constants [e.g., 10a showed d 3.30 (dt, J = 11.8,
4.8 Hz, 1H, 4-H), 2.82 (dd, J = 12.0, 6.1 Hz, 1H, 2-H),
1.96 (ddd, J = 12.1, 4.8, 1.6 Hz, 1H, 5-Heq)] and on
the basis of previous studies.1a,b,e,6 The stereochemical
assignments were further confirmed after converting
10a–c to the final lactones 1, 2 and 3, whose spectral
data were identical in all respects with those reported.
The 6-pyranyl methanols 12a–c were obtained quantita-
tively from 10a–c after methoxymethyl protection of the
2° alcohol in the presence of diisopropylethylamine and
deprotection of the resulting benzyl ether with Li in
liquid ammonia. The alcohols 12a–c on treatment with
PCC in refluxing benzene afforded the lactones 13a–c
in 85–90% yields.14 Deprotection of the methoxymethyl
ether with 1 N HCl in THF furnished the prelactones 1,
To carry out the crucial prins cyclisation reactions, a
mixture of 9 and an aldehyde was treated with amber-
lyst-151c in refluxing DCM for 5–6 h to produce the
tetrasubstituted tetrahydropyrans 10a–c in 48–55%
yields along with 30–34% of recovered 9. Whereas, the

J. S. Yadav et al. / Tetrahedron Letters 46 (2005) 2133–2136
2135
2 and 3 in 82–86% yields. The spectroscopic (1H NMR,
13C NMR, IR, mass) and physical data15 (specific rota-
tions and melting points) of all the lactones were in
good agreement with those reported.11,12
9. (a) Endo, J. A. J. Med. Chem. 1985, 28, 401–405; (b)
Honda, T. J. Chem. Soc., Perkin Trans. 1 1990, 1733–
1737; (c) Argoudelis, A. D.; Zieserl, J. F. Tetrahedron Lett.
1966, 18, 1969–1973; (d) Cavil, G. W. K.; Clark, D. V.;
Whitefield, F. B. Aust. J. Chem. 1968, 21, 2819–2823; (e)
Laurence, B. R. J. Chem. Soc., Chem. Commun. 1982, 59.
10. (a) Sato, M.; Nakashima, H.; Keisuke, H.; Hayashi, M.;
Honzumi, M.; Taniguchi, T.; Ogasawara, K. Tetrahedron
Lett. 2001, 42, 2833–2837; (b) Wilkinson, A. L.; Hanefeld,
U.; Wilkinson, B.; Leadlay, P. F.; Staunton, J. Tetra-
hedron Lett. 1998, 39, 9827–9830; (c) Hinterding, K.;
Singhanat, S.; Oberer, L. Tetrahedron Lett. 2001, 42,
8463–8465; (d) Wu, Y.; Shen, X.; Tang, C.-J.; Chen, Z. L.;
Hu, Q.; Shi, W. J. Org. Chem. 2002, 11, 3802–3810.
11. For the synthesis of prelactone B, see (a) Yadav, J. S.;
Reddy, K. B.; Sabitha, G. Tetrahedron Lett. 2004, 45,
6475–6476; (b) Aggarwal, V. K.; Bae, I.; Lee, H.-Y.
Tetrahedron 2004, 60, 9725–9733; (c) Dias, L. C.; Steil, L.
J.; Vasconcelos, V. de A. Tetrahedron: Asymmetry 2004,
15, 147–150; (d) Pihko, P. M.; Erkkila, A. Tetrahedron
Lett. 2003, 44, 7607–7609; (e) Chakraborty, T. K.;
Tapadar, S. Tetrahedron Lett. 2003, 44, 2541–2543; (f)
Fournier, L.; Gaudel-sin, A.; Kocienski, P. J.; Pons, J.-M.
Synlett 2003, 107–111; (g) Csak, A. G.; Mba, M.; Plumet,
J. Synlett 2003, 2092–2094; (h) Enders, D.; Haas, M.
Synlett 2003, 2182–2184; (i) Hanefeld, U.; Hooper, A. M.;
Staunton, J. Synthesis 1999, 38, 401–403.
In conclusion, a flexible and efficient approach to the
asymmetric synthesis of triketide d-lactones such as
(+)-prelactones B, C and V has been described involving
Prins cyclisation as the key step. A variety of functional-
ised chains can be installed at C-3, C-5 and C-6 of the
lactones. Further applications of the methodology in
the synthesis of several complicated chiral intermediates
for polyketide synthesis are in progress and the results
will be published in due course.
Acknowledgements
M.S.R. thanks CSIR, New Delhi for the award of
fellowship.
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2. See for example: (a) Zhang, W.-C.; Viswanathan, G. S.;
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7. (a) Cortes, J.; Wiesman, K. E. H.; Roberts, G. A.; Brown,
M. J. B.; Staunton, J.; Leadlay, P. F. Science 1995, 268,
1487–1489; (b) Kao, C. M.; Luo, G.; Katz, L.; Cane, D.
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150–157; (d) Gerlitz, M.; Hammann, P.; Thiericke, R.;
Rohr, J. J. Org. Chem. 1992, 57, 4030–4033.
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Saito, S.; Ishitani, H.; Kobayashi, S. J. Am. Chem. Soc.
2003, 125, 3793–3798; (b) Chakraborty, T. K.; Tapadar, S.
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15. Selected physical data for compound 1. Rf = 0.45 (silica,
20
60% EtOAc in petroleum ether); ½aꢁD +36.8 (c 0.72,
MeOH); mp 97–98 °C; IR (KBr): mmax 3475, 2969, 2925,
;
1718, 1465, 1274, 1004 cmꢀ1 1H NMR (200 MHz,
CDCl3): d 3.72 (m, 2H), 2.89 (dd, J = 17.6, 5.9 Hz, 1H),
2.52 (br s, OH, 1H), 2.48 (dd, J = 17.8, 8.0 Hz, 1H), 1.98
(m, 1H), 1.76 (ddq, J = 10.0, 7.0, 6.1 Hz, 1H), 1.12 (d,
J = 6.0 Hz, 3H), 1.08 (d, J = 6.0 Hz, 3H), 0.92 (d,
J = 6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 171.33,
86.38, 69.65, 38.96, 38.89, 28.89, 19.94, 14.04, 13.60;
EIMS: m/z (%) 129 (M+ꢀC3H7, 25), 111 (23), 87 (28), 58
(55), 43 (100). Anal. Calcd for C9H16O3 (172.22): C, 62.77;
H, 9.36%. Found: C, 62.84; H, 9.41%. Compound 2.
20
Rf = 0.5 (silica, 70% EtOAc in petroleum ether); ½aꢁD
+54.4 (c 0.76, MeOH); IR (neat): mmax 3400, 2925, 1730,
1225 cmꢀ1 1H NMR (200 MHz, CDCl3): d 5.79 (ddq,
;
J = 15.2, 6.6, 1.0 Hz, 1H), 5.43 (ddq, J = 15.2, 8.2, 2.0 Hz,
1H), 4.17 (dd, J = 10.4, 8.2 Hz, 1H), 3.74 (ddd, J = 8.0,
7.0, 5.8 Hz, 1h), 3.07 (br s, OH, 1H), 2.87 (dd, J = 17.0,
5.8 Hz, 1H), 2.46 (dd, J = 17.0, 8.0 Hz, 1H), 1.77 (dd,
J = 6.6, 2.0 Hz, 3H), 1.64 (ddq, J = 10.4, 7.0, 6.8 Hz, 1H),
1.02 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
170.34, 132.41, 127.61, 84.11, 69.53, 41.49, 39.08, 17.62,
13.66; EIMS: m/z (%) 152 (M+ꢀH2O, 14), 109 (10), 82
(40), 71 (100), 58 (31), 43 (53). Anal. Calcd for C9H14O3
(170.20): C, 63.51; H, 8.29%. Found: C, 63.46; H, 8.31%.
Compound 3. Rf = 0.4 (silica, 60% EtOAc in petroleum
25
8. Khosla, C.; Gokhale, R. S.; Jacobsen, J. R.; Cane, D. E.
Ann. Rev. Biochem. 1999, 68, 219–253, and references cited
therein.
ether); ½aꢁD +32.8 (c 0.98, MeOH); mp 46 °C; IR (KBr):
mmax 3435, 2980, 2932, 1730, 1383, 1267, 1095, 1046,
979 cmꢀ1 1H NMR (200 MHz, CDCl3): d 3.93 (dt,
;

2136
J. S. Yadav et al. / Tetrahedron Letters 46 (2005) 2133–2136
J = 5.7, 7.2 Hz, 1H), 3.75 (dq, J = 6.2, 10.1 Hz, 1H), 2.9
NMR (75 MHz, CDCl3): d 170.53, 79.04, 69.67, 43.32,
39.07, 19.55, 13.71; EIMS: m/z (%) 144 (M+, 50), 102
(100), 71 (75), 41 (95). Anal. Calcd for C7H12O3 (144.16):
C, 58.32; H, 8.39%. Found: C, 58.26; H, 8.44%.
(dd, J = 5.6, 16.6 Hz, 1H), 2.42 (dd, J = 7.2, 16.6 Hz, 1h),
1.98 (br s, OH, 1H), 1.58 (ddq, J = 10.2, 7.2, 6.8 Hz, 1H),
1.38 (d, J = 6.2 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H); 13C