Stereoselective total synthesis of (+)-cryptocarya diacetate by an iterative Jacobsen's hydrolytic kinetic resolution protocol

Article abstract of DOI:10.1016/j.tetlet.2005.03.202

A combination of iterative Jacobsen's hydrolytic kinetic resolution and reduction of a ketone for the construction of a 1,3-polyol moiety are key steps en route to a total synthesis of (+)-cryptocarya diacetate.

Full text of DOI:10.1016/j.tetlet.2005.03.202

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3905–3907
Stereoselective total synthesis of (+)-cryptocarya diacetate by
an iterative Jacobsen’s hydrolytic kinetic resolution protocolI
Palakodety Radha Krishna* and V. V. Ramana Reddy
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 28 January 2005; revised 14 March 2005; accepted 23 March 2005
Available online 14 April 2005
Abstract—A combination of iterative JacobsenÕs hydrolytic kinetic resolution and reduction of a ketone for the construction of a
1,3-polyol moiety are key steps en route to a total synthesis of (+)-cryptocarya diacetate.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Cryptocarya diacetate 1, the simplest 6-substituted 5,6-
dihydropyran-2-one, was isolated along with other
structurally similar compounds from the leaves and bark
of the South African plant Cryptocarya latifolia that has
long been noted for its legendary medicinal properties.1
These properties range from the treatment of headaches
and morning sickness to that of cancer, pulmonary
diseases, and various bacterial and fungal infections.2
The retrosynthetic analysis, as depicted in Scheme 1,
envisions that 1 could be obtained from 2 by functional
group transformations, elaboration, and lactonization
while 2 in turn could be visualized from 3 by a Jacob-
senÕs hydrolytic kinetic resolution (HKR) and reductive
ring-opening reaction of a chiral epoxide. Compound 3
in turn could conveniently be derived from 4 by diaste-
reoselective reduction to afford the syn-1,3-diol struc-
tural unit, while 4 was to be obtained from 5 by
allylation of the aldehyde generated by ozonolysis fol-
lowed by oxidation of the ensuing alcohol and desilyl-
ation. Similarly 5 could be obtained from the known
epoxide 6 (obtained by JacobsenÕs HKR of a homoall-
ylic alcohol derivative) through a ring-opening reaction
with vinylmagnesium bromide and subsequent hydroxyl
group protection.
OAc
OAc
O
O
(+)-cryptocarya diacetate 1
Earlier syntheses3a–c of 1 were based either on Sharpless
asymmetric epoxidation3a and regioselective ring open-
ing as the key steps, or involved an enantioselective syn-
thesis from ethyl sorbate by a Sharpless asymmetric
dihydroxylation-RCM strategy.3b,c Herein a stereoselec-
tive total synthesis of 1 is reported, using a combination
of JacobsenÕs hydrolytic kinetic resolution and diaste-
reoselective ketone reduction to garner the required
chiral centers.
The known4 epoxide 6 on exposure to vinylmagnesium
bromide in THF afforded a homoallylic alcohol in good
yield (74%) that was then protected as its TBS ether 5
(82%) with TBSCl in CH2Cl2 at room temperature
(Scheme 2). Reductive ozonolysis of olefin 5 afforded
an aldehyde 7, which was immediately converted to
homoallylic alcohol 8 (82%) with allyl bromide/Zn,
subsequent PCC oxidation in the presence of NaOAc
providing ketone 4a (72%). Desilylation of 4a with
HF–pyridine gave b-hydroxy ketone 4 in 63% yield.
Selective reduction of 4 with NaBH4 in the presence of
the chelating agent B(Et)2OMe5 in THF resulted in
exclusive formation of the syn-1,3-diol (de > 98%),
which was characterized as acetonide 3 (94%), prepared
under conventional reaction conditions using 2,20-DMP
in DMSO catalyzed by PTSA. The stereochemical
assignment of the newly created center was made based
Keywords: Jacobsen hydrolytic kinetic resolution; a,b-unsaturated
d-lactone; 1,3-syn-polyol.
q IICT Communication No. 050111.
*
Corresponding author. Fax: +91 40 271 60387/+91 40 271 60757;
e-mail: prkgenius@iict.res.in
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.202

3906
P. Radha Krishna, V. V. Ramana Reddy / Tetrahedron Letters 46 (2005) 3905–3907
OBn
OBn
OAc O
OBn
O
OAc OAc O
O
O
3
1
2
O
OBn
OBn
O
O
OH
OTBS
6
5
4
Scheme 1.
a
OBn
b
OBn
OBn
OBn
OBn
OHC
O
6
7 OTBS
5
OTBS
OBn
c
d
OTBS
OH
O
OR
4a R = TBS
8
4 R = H
e
f
OBn
O
O
O
O
O
9
3
h
g
+
OBn
OBn
OAc O
O
HO
OH
O
O
2
9a
i
O
H
H
N
N
j
Co
OCH3
O
1
O
OAc
OAc O
O
10
(R, R)-(salen)CoIII(OAc)
A
Scheme 2. Reagents and conditions: (a) (i) vinylmagnesium bromide, THF, CuI, rt, 74%, (ii) TBSCl, imidazole, rt, 82%; (b) O3, CH2Cl2, 78 ꢁC, 0.5 h,
then Me2S, rt, 0.5 h; (c) allyl bromide, Zn NH4Cl, THF, rt, 82%; (d) PCC, NaOAc, CH2Cl2, rt, 72%; (e) (i) HF–pyridine, THF, rt, 63%, (ii)
B(Et)2OMe, NaBH4, THF, 75%, (iii) 2,20-dimethoxypropane, PTSA, DMSO, 94%; (f) (i) oxone, acetone, NaHCO3, EDTA (cat.) 73%, (ii) (R,R)-
(salen)CoIII(OAc) A, 0.55 equiv H2O, 43%; (g) (i) LAH, THF, rt, 89%, (ii) Ac2O, pyridine, DMAP (cat.), CH2Cl2, rt, 94%; (h) (i) PhCOCl, Et3N,
CH2Cl2, rt, (ii) TsCl, Et3N, CH2Cl2, rt, (iii) K2CO3, MeOH, rt; (i) (i) Pd/C, H2, EtOAc, rt, 95%, (ii) IBX, DMSO, rt, (iii) (F3CCH2O)2POCH2
COOMe, KH MDS, 18-crown-6, THF, 78 ꢁC, 79% over two steps; (j) (i) 80% aq AcOH, (ii) PTSA, C6H6, (iii) Ac2O, pyridine, CH2Cl2, DMAP (cat.),
rt, 86% over three steps.
on RychnovskyÕs analogy6 wherein the 13C NMR spec-
tra of 3 exhibited acetonide methyl carbons at d 19.8 and
30.2 characteristic of the acetonide of a syn-1,3-diol
moiety.
Next, reductive ring-opening of epoxide 9 with LAH
gave the secondary alcohol (89%), which was acetylated
(Ac2O/pyridine/CH2Cl2/rt) to afford 2 (94%). Removal
of the benzyl protecting group (Pd–C/H2/EtOAc/rt) in
2 (95%) released the terminal hydroxyl group, the subse-
quent oxidation of which by IBX in DMSO at room
temperature gave the aldehyde, which was then chain
elongated on reaction with a Wittig ylide to provide
the corresponding a,b-unsaturated ester 10 (F3CCH2O)2
POCH2COOMe, KHMDS, 18-crown-6, THF, ꢂ78 ꢁC,
79% over two steps) predominantly as the (Z)-isomer,8
as characterized by 1H and 13C NMR spectroscopy.
For example the coupling constant (J = 6.8 Hz) of the
olefinic protons confirmed the (Z)-geometry of olefin.
Finally, acid catalyzed deprotection of the acetonide
group (80% aq AcOH), concomitant cyclization under
PTSA conditions and acetylation (Ac2O/pyridine/
CH2Cl2/rt) afforded the target compound 1 (86% over
Epoxidation of 3 with oxone furnished the epoxide and
JacobsenÕs hydrolytic kinetic resolution4 with 0.55 equiv
of water using (R,R)-(salen)CoIII(OAc) A as the catalyst
provided enantiomerically pure 9 and diol 9a in 43%
yield each. The chiral homogeneity of both
9
(de ꢀ 94%) and 9a was confirmed by HPLC analysis.7
Diol 9a was recycled to 9 by a three-step sequence. Thus,
9a was mono benzoylated (BzCl/Et3N/CH2Cl2/rt) fol-
lowed by tosylation of the secondary hydroxyl (TsCl/
Et3N/CH2Cl2/DMAP/rt) to give the diprotected com-
pound. Base induced deprotection of the benzoate gen-
erated an alkoxide, which prompted simultaneous
elimination of tosylate and ring closure by an SN2 mode
25
D
CHCl3) in 58% yield over three steps (de 80%).
25
25
to afford the desired epoxide 97 ½aꢁ +16.3 (c 0.5,
three steps), ½aꢁ +55.4 (c 0.3, CHCl3); lit.1 ½aꢁ +55.8
D
D
(c 1.06, CHCl3). The spectral data of synthetic 19 were

P. Radha Krishna, V. V. Ramana Reddy / Tetrahedron Letters 46 (2005) 3905–3907
3907
in accordance with those of the natural product.1 The
synthesis of 1 also established the assigned stereochem-
istry of 9.
Chiralcel OBH 250 · 4.6 mm, PDA detector at 254 nm,
10% EtOH, 10% iPrOH, 80% n-hexane, flow rate 1 mL/min,
tr(minor) = 4.58 min, tr(major) = 4.96 min with a diastereo-
meric ratio of 1.0:9.0.
8. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–
4408.
In conclusion, the stereoselective synthesis of (+)-cryp-
tocarya diacetate was accomplished by a combination
of JacobsenÕs hydrolytic kinetic resolution of a multichi-
ral synthon and diastereoselective ketone reduction
as the key steps for installing the chiral centers of the
1,3-polyol system and subsequent elaboraation to the
a,b-unsaturated-d-lactone moiety.
25
9. Spectral data for selected compounds: Compound 3: ½aꢁD
1
+5.2 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3): d 1.33,
1.4 (2 · s, 6H, 2 · CH3), 1.44 (t, J = 3.0 Hz, 1H, –CH2),
1.48 (t, J = 3.0 Hz, 1H, –CH2), 1.68 (m, 2H, –CH2), 2.1 (m,
1H, –CH2), 2.25 (m, 1H, –CH2), 3.43–3.58 (m, 2H,
–CH2OBn), 3.82 (m, 1H, –CH), 3.97 (ddt, J = 2.3, 5.3,
7.5 Hz, 1H, –CH), 4.45 (d, J = 2.3 Hz, 2H, –OCH2Ph), 5.0–
5.07 (m, 2H, –CH@CH2), 5.67–5.82 (m, 1H, –CH@CH2),
7.27 (br s, 5H, Ar-H); 13C NMR (75 MHz, CDCl3): 19.8,
30.2, 36.5, 40.8, 66.1, 66.2, 68.6, 72.9, 116.9, 127.5, 127.6,
128.3, 134.2; IR (neat): 2942, 1645, 1378, 1268, 1198,
1102 cmꢂ1; EIMS: 290 (M+). Anal. Calcd for C18H26O3: C,
74.45; H, 9.02%. Found: C, 74.48; H, 9.03%. Compound
Acknowledgements
One of us (V.V.R.R.) thank the UGC, New Delhi, for
financial support in the form of a research fellowship.
25
10: ½aꢁD +27.7 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3):
1.20 (d, J = 6.0 Hz, 3H, –CH3), 1.33–1.6 (m, 10H, 2 · CH2
and 2 · CH3), 2.0 (s, 3H, –OAc), 2.7 (ddq, J = 2.2, 4.5,
6.8 Hz, 1H, CH2), 2.90 (ddq, J = 2.3, 3.7, 6.9 Hz, 1H, CH2),
3.69 (s, 3H, –COOCH3), 3.78–3.94 (m, 2H, –CH), 5.05 (m,
1H, –CHOAc), 5.80 (dd, J = 2.2, 6.8 Hz, 1H, –CH@CH),
6.36 (ddd, J = 1.5, 2.5, 6.0 Hz, 1H, –CH@CH); 13C NMR
(75 MHz, CDCl3): 19.5, 20.1, 20.7, 21.3, 30.1, 35.5, 36.7,
42.8, 50.0, 65.5, 67.6, 67.9, 68.4, 120.6, 145.9, 146.0; EIMS
References and notes
1. Drewes, S. E.; Sehlapelo, B. M.; Horn, M. M.; Scott-Shaw,
R.; Sandor, P. Phytochemistry 1995, 38, 1427–1430.
2. Sam, T. W.; Yeu, C. S.; Jodynis-Liebert, J.; Murias, M.;
Bloszyk, E. Planta Med. 2000, 66, 199–205.
3. (a) Jorgensen, K. B.; Suenaga, T.; Nakata, T. Tetrahedron
Lett. 1999, 40, 8855–8858; (b) Hunter, T. J.; OÕDoherty, G.
A. Org. Lett. 2001, 3, 2777–2780; (c) Smith, G. M.;
OÕDoherty, G. A. Org. Lett. 2003, 5, 1959–1962.
4. (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E.
N. Science 1997, 277, 936–938; (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, 1307–1315.
314 (M+); IR (neat): 2922, 2853, 1720, 1649, 1340 cmꢂ1
.
Anal. Calcd for C16H26O6: C, 61.13; H, 8.34%. Found: C,
61.12; H, 8.36%. Compound 1: [a]D +55.4 (c 0.3, CHCl3);
lit.1 [a]D +55.8 (c 1.06, CHCl3; 1H NMR (300 MHz,
CDCl3): d 1.27 (d, J = 6.8 Hz, 3H, –CH3), 1.79 (ddd,
J = 6.0, 8.0, 14.3 Hz, 1H, –CH2), 1.97 (ddd, J = 4.0, 6.6,
14.3 Hz, 1H, –CH2), 2.00 (ddd, J = 6.0, 8.0, 14.3 Hz, 1H,
–CH2), 2.04 (s, 3H, –OCH3), 2.07 (s, 3H,–OCH3), 2.16
(ddd, J = 1.0, 4.0, 6.0 Hz, 1H, –CH2), 2.31 (m, 1H, –CH2),
2.5 (ddd, J = 1.0, 5.0, 18.0 Hz, 1H, –CH2), 4.5 (ddd, J = 3.8,
6.7, 11.0 Hz, 1H, –CH), 5.0 (m, 1H, CH), 5.11 (dddd,
J = 4.5, 6.0, 7.2, 9.0 Hz, 1H, –CH), 6.02 (ddd, J = 0.75, 3.0,
9.8 Hz, 1H, CH), 6.88 (ddd, J = 0.75, 3.0, 6.7 Hz, 1H,
–CH); 13C NMR: 20.1, 21.1, 29.3, 39.2, 40.5, 67.7, 67.8,
74.9, 121.4, 144.6, 163.8, 170.5, 170.6; FABMS (m/z): 307
(M++23, 12), 285 (M++1, 22), 225 (40), 154 (100), 137
5. Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.;
Prasad, K.; Repic, O.; Shapiro, M. J. Chem. Lett. 1987,
1923–1926.
6. Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990,
31, 945–948.
25
7. Compound 9: ½aꢁD +21.3 (c 0.5, CHCl3); HPLC analysis:
Column: Chiralcel OBH 250 · 4.6 mm, PDA detector at
254 nm, 10% EtOH, 10% PrOH, 80% n-hexane, flow rate
i
1 mL/min, tr(minor) = 4.56 min, tr(major) = 4.97 min with
a diastereomeric ratio of 0.3:9.7. Recycled compound 9:
(96), 107 (92); IR (neat): 2980, 1730, 1434, 1238, 1037 cmꢂ1
.
Anal. Calcd for C14H20O6: C, 59.15; H, 7.09%. Found: C,
59.18; H, 7.11%.
25
½aꢁD +16.3 (c 0.5, CHCl3); HPLC analysis: Column: