Stereoselective total synthesis of (+)-(6R,2′S)-cryptocaryalactone and (-)-(6S,2′S)-epi cryptocaryalactone via asymmetric acetate aldol reaction

Article abstract of DOI:10.1016/j.tetlet.2012.02.073

The total synthesis of (+)-(6R,2′S)-cryptocaryalactone and (-)-(6S,2′S)-epi cryptocaryalactone is reported based on asymmetric acetate aldol reaction. Still-Gennari reaction, Evans acetal intramolecular oxa-Michael reaction and lactonisation are the key s

Full text of DOI:10.1016/j.tetlet.2012.02.073

Tetrahedron Letters 53 (2012) 2496–2499
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Tetrahedron Letters
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Stereoselective total synthesis of (+)-(6R,20S)-cryptocaryalactone and
(ꢀ)-(6S,20S)-epi cryptocaryalactone via asymmetric acetate aldol reaction
⇑
J. S. Yadav , Dinesh C. Bhunia, B. Ganganna
Natural Products Chemistry Division, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
The total synthesis of (+)-(6R,20S)-cryptocaryalactone and (ꢀ)-(6S,20S)-epi cryptocaryalactone is reported
based on asymmetric acetate aldol reaction. Still–Gennari reaction, Evans acetal intramolecular oxa-
Michael reaction and lactonisation are the key steps in the target synthesis.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 1 December 2011
Revised 15 February 2012
Accepted 16 February 2012
Available online 5 March 2012
Keywords:
a,b-Unsaturated d-lactone
Asymmetric aldol reaction
Still–Gennari reaction
Cryptocaryalactone
Cryptocarya bourdilloni
Substituted
a
,b-unsaturated d-lactones (e.g., styryllactones) are
an efficient synthesis of (+)-(6R,20S)-cryptocaryalactone and
(ꢀ)-(6S,20S)-epi cryptocaryalactone through asymmetric acetate
aldol reaction as the key reaction.
an important class of natural products displaying a broad range of
potent biological activities.1 Over the past two decades an increas-
ing number of
a-pyrones have been isolated from a variety of
sources. Goniothalamin, (+)-(6R,20S)-cryptocaryalactone, (ꢀ)-
(6S,20S)-epi cryptocaryalactone, kurzilactone, cryptomoscatone
D2, (+)-cryptofolione and (+)-obolactone are some of the naturally
occurring styryl lactones (Fig. 1). All of these compounds exhibit
some biological activities, for example goniothalamin exhibits
antifungal, immunosuppressive and anti-inflammatory activity.2
Cryptocaryalactones are natural germination inhibitors with no ef-
fect on corn3 whereas kurzilactone and obolactone exhibits cyto-
toxicity against KB cells.4 Cryptomoscatone D2 showed dose- and
time-dependent cytotoxicity and is a highly efficacious inhibitors
of the G2 check point.5 (+)-Cryptofolione is active against the try-
pomastogotes of Trypanosoma cruzi, reducing their number by
O
O
OAc O
O
1
Goniothalamin ( )
2
(+)-(6R,2S) -Cryptocaryalactone ( ).
O
O
OAc O
O
OH
O
4
Kurzilactone ( )
77% at 250 l
g/mL.6 At least some of these pharmacological effects
(-)-(6S,2'S)-epi Cryptocaryalactone (3).
O
O
may be related to the presence of the conjugated double bond,
which acts as a Michael acceptor. (+)-(6R,20S)-Cryptocaryalactone
was isolated from Cryptocarya bourdilloni GAMB (Lauraceae) by
Govindachari in 19727 and its absolute stereochemistry was
established by H. H. Meyer through stereoselective synthesis.8
There are three reports on the synthesis of (+)-(6R,20S)-cryptocary-
alactone9 and one for (ꢀ)-(6S,20S)-epi cryptocaryalactone.8
OH OH
O
OH OH
O
6
(+)-Cryptof olione ( )
5
Cryptomoscatone D2 ( )
O
O
We were interested in synthesizing natural products containing
5,6-dihydro-2H-pyran-2-one moiety10 and herein we described
O
O
H
H
7
(+)-Obolactone ( )
Figure 1. Some natural products containing Styryl lactones.
⇑
Corresponding author. Fax: +91 40 27160387.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.073

J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 2496–2499
2497
O
O
O
S
CHO
TiCl4, DIPEA
OAc O
OAc O
N
oC
S
, - 78
CH2Cl2
11
1 h, 82%
12
2
3
Ph
OH
O
OH
O
S
S
(-)-(6S,2'S)-ep i Cryptocaryalactone.
(+)-(6R,2'S)-Cryptocaryalactone
N
N
S
S
10a
10
Ph
TBSO
OH
minor
major
Ph
Ph
O
O
anti product
O
S
synproduct
(95:5)
8
COOMe
S
TBSO
13
COOMe
TBSOTf, 2,6-lutidine
DIBAL-H, CH2Cl2
-78 oC, 10 min
N
S
CH2Cl2,0 oC
15
30 min, 92%
82%
TBSO
OH
O
Ph
Ph
N
S
O
O
O
O
N
TBSO
16
O
S
9
O
N
TiCl4, DIPEA
CH2Cl2, - 78 oC,
78%
H
14
Ph
S
17
Ph
S
TBSO
OH
O
S
OH
O
S
TBSO
OH
O
S
N
N
S
N
S
9a
9
10
Ph
(95:5)
Ph
Ph
Ln
O
S
S
Ti
O
S
O
CHO
S
S
O
OH
Ph
N
S
N
TiCl4
S
a
S
N
S
N
H
N
R
S
11
TiLn
R
O
12
H
Ph
O
Ph
acetate syn
Ph
Ph
H
Scheme 1. Retrosynthetic analysis of (+)-(6R,20S)-cryptocaryalactone and (ꢀ)-
(6S,20S)-epi-cryptocaryalactone.
a.TiCl4, DIPEA, RCHO, -780C, CH2Cl2
R = trans -cinnamaldehyde
Scheme 2. Synthesis of intermediate 9.
The retrosynthetic analyses for compound 2 and 3 are depicted
in Scheme 1. The target molecule 2 could be obtained from 8 by
acid catalyzed lactonisation, deprotection of TBS group and acety-
lation. Compound 8 in turn could be obtained from 9 via Still–Gen-
nari Wittig olefination. The compound 9 can be synthesized from
10, which in turn obtained from trans-cinnamaldehyde 11 via
asymmetric acetate aldol reaction with (R)-1-(4-benzyl-2-thioxo-
thiazolidin-3-yl) ethanone 12. The compound (ꢀ)-(6S,20S)-crypto-
caryalactone 3 could be obtained from 13 by acid catalyzed one
pot benzylidene acetal deprotection, lactonisation and followed
by acetylation.9b
The synthesis of the target molecule 2 (Scheme 2) began with
an asymmetric acetal aldol reaction11 of (R)-1-(4-benzyl-2-thioxo-
thiazolidin-3-yl)ethanone 12 and trans-cinnamaldehyde 11 in the
presence of titanium (IV) chloride and diisopropylethylamine in
CH2Cl2 at ꢀ78 °C to afford aldol product 1011d–f as major diastereo-
mer (95:5, after isolated yield).The hydroxyl group in compound
10 was protected as TBS ether 15 using TBSOTf, 2,6-lutidine in
CH2Cl2 at 0 °C in 92% yield. The compound 15 was reduced with
DIBAL-H at ꢀ78 °C in CH2Cl2 to afford the corresponding aldehyde,
which was directly subjected to asymmetric acetate aldol reaction
with (S)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethanone 17 to ob-
tain 9 as major diastereomer in 78% yield (95:5, after isolated
yield) (Scheme 2). Suggested transition states for the titanium
mediated acetate aldol reactions are given below.
TBSO
OH
O
S
1. DIBAL-H, THF, 30 min,
- 78 oC, 88%
N
S
9
2. (CF3CH2O)2POCH2COOMe
NaH, THF, - 78 oC,
1 h, 82%
Ph
TBSO
TBSO
OH
O
CSA, benzene
0 oC, 1 h, 92%
8
COOMe
O
O
OH
O
4 N HCl, THF
0 oC-rt, 2 h, 82%
19
O
18
OAc O
Ac2O, Et3N, DMAP
CH2Cl2, 0 oC, 1 h,
2
85%
(+)-( 6R,2'S)-Cryptocaryalactone
Scheme 3. Synthesis of (+)-(6R,20S)-cryptocaryalactone.
The compound 9 was treated with DIBAL-H to get the corre-
sponding aldehyde, which was then subjected to Still–Gennari
reaction with bis(2,2,2-trifluoroethyl)(methoxy carbonylmeth-
urated ester 8 exclusively as the (Z)-isomer in 82% yield (Scheme
3). The compound 8 on treatment with camphorsulfonic acid
(CSA) in benzene at 0 °C afforded the lactone 18 in 92% yield, which
yl)phosphonate12 in THF at ꢀ78 °C for 1 h to afford the
a,b-unsat-

2498
J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 2496–2499
OH
O
1. DIBAL-H, THF,
Acknowledgment
S
- 78 oC, 20 min, 85%
N
S
D. C. B. and B. G. thank CSIR, New Delhi for financial assistance
in the form of fellowship.
10
2. 20, DBU, LiCl
CH3CN:CH2Cl2 = 3:1
Ph
0 oC to rt, 4 h, 78%
Supplementary data
OH
O
PhCHO, KOtBu
THF, 0 oC, 4 h, 87%
O
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.073.
21
Ph
References and notes
1. DIBAL-H, THF,
- 78 oC, 91%
O
O
O
O
O
1. (a) Yasui, K.; Tamura, Y.; Nakatani, T.; Kawada, K.; Ohtani, M. J. Org. Chem. 1995,
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Said, I. M. Phytother. Res. 2001, 15, 681–686.
3. Drewes, S. E.; Horn, M. M.; Ramesar, N. S.; Ferreira, D.; Nel, R. J. J.; Hutchings, A.
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A.; Ferreira, M. E.; Inchaustti, A.; Yaluff, G. J. Pharm. Pharmacol. 2001, 53,
563576.
N
2. (CF3CH2O)2POCH2COOMe
14
NaH, THF, - 78 o
1 h, 90%
C
Ph
O
4N HCl, THF
0 oC, 4 h, 85%
COOEt
13
O
O
OH
O
Ac2O, Et3N, DMAP
CH Cl , 1
h, 88%
2
2
22
OAc O
O
P
O
EtO
EtO
O
N
20
3
(-)-(6S,2'S)-epi cryptocaryalactone 3.
7. Govindachari, T. R.; Parthasarathy, P. C.; Modi Indian J. Chem. 1972, 10, 149–
151.
8. Meyer, H. H. Leibigs Ann. Chem. 1984, 977–981.
Scheme 4. Synthesis of (ꢀ)-(6S,20S)-epi cryptocaryalactone.
9. (a) Mori, Y.; Furukawa, H. Chem. Pharm. Bull. 1994, 42, 2161–2163; (b) Sabitha,
G.; Bhaskar, V.; Reddy, S. S. S.; Yadav, J. S. Tetrahedron 2008, 64, 10207–10213;
(c) Radha Krishna, P.; Krishnarao, L.; Reddy, K. L. N. Beilstein J. Org. Chem. 2009,
5. doi:10.3762/bjoc.5.14.
10. (a) Sabitha, G.; Sudhakar, K.; Yadav, J. S. Tetrahedron Lett. 2006, 47, 8599–8602;
(b) Sabitha, G.; Bhaskar, V.; Reddy, S. S. S.; Yadav, J. S. Helv. Chim. Acta 2010, 93,
329–338; (c) Sabitha, G.; Reddy, S. S. S.; Reddy, D. V.; Bhaskar, V.; Yadav, J. S.
Synthesis 2010, 20, 3453–3460.
11. (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775–777; (b) Hodge, M. B.;
Olivo, H. F. Tetrahedron 2004, 60, 9397–9403; (c) Crimmins, M. T.; King, B. W.;
Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894–902; (d) Yadav, J. S.;
Kumar, V. N.; Rao, R. S.; Srihari, P. Synthesis 2008, 1938–1942; (e) Srihari, P.;
Ragendar, G.; Srinivasa Rao, R.; Yadav, J S Tetrahedron Lett. 2008, 49, 5590–
5592; (f) Srihari, P.; Satyanarayana, K.; Ganganna, B.; Yadav, J. S. J. Org. Chem.
2011, 6, 1922–1925.
12. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
13. Etavo, P.; Badorrey, R.; Diaz-de-Villegas, M. D.; Galvez, J. A. J. Org. Chem. 2007,
72, 1005–1008.
was treated with 4 N HCl in THF to give the alcohol 19 in 82% yield.
Finally compound 19 was acetylated with acetic anhydride and tri-
ethylamine in the presence of catalytic amount of DMAP in CH2Cl2
to furnish the target compound 2 as a solid in 85% yield (Scheme
3), {mp 124–126 °C/lit. 126–127 °C and
½
a 2D5
= +18.2 (c 0.2
ꢁ
CHCl3)/lit8 +19.0 (c 0.67)}. The spectral data of the synthetic com-
pound 216 were in accordance with those of the natural product.7
Now for the synthesis of (ꢀ)-(6S,20S)-epi cryptocaryalactone, we
started from compound 10. Compound 10 was reduced with DI-
BAL-H to obtain corresponding aldehyde, which was subjected to
Wittig reacton13 with N-methoxy N-methyl diethylphosphonoace-
tamide14 20 to afford the
a,b-unsaturated amide 21 exclusively as
14. Nuzillard, J. M.; Boumendjel, A.; Massiot, G. Tetrahedron Lett. 1989, 29, 3779–
3780.
E-isomer. The compound 21 was subjected to an Evans acetal intra-
molecular oxa-Michael reaction with benzaldehyde and potassium
tert-butoxide to yield the product 14 in 87% yield15 (Scheme 4).
The compound 13 was treated with DIBAL-H in THF at ꢀ78 °C to
obtain aldehyde which was subjected to Still–Gennari12 reaction
with bis(2,2,2-trifluoroethyl)(ethoxy carbonylethyl)phosphonate
in THF at ꢀ78 °C to get the key precursor 13 in 90% yield (Scheme
4).12 The deprotection of benzylidene acetal followed by concomi-
tant lactonization was achieved with 4 N HCl in THF at 0 °C to ob-
tain 22 in 85% yield. Finally compound 22 was acetylated with
acetic anhydride and triethylamine in the presence of catalytic
amount of DMAP in CH2Cl2 to furnish the target compound 3 in
88% yield as a yellowish liquid (Scheme 4). The spectroscopic data
of synthetic compound 316 are in agreement with those reported
for the natural one.8
15. Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446–2453.
16. The 1H and 13C NMR spectral data and optical rotation, of the synthetic
compounds 2 and 3 are identical with the reported values. Spectroscopic data
for selected compounds are given below. Compound 2. White solid. mp 124–
126 °C;½a 2D5
ꢁ
= +18.5 (c 0.2, CHCl3); IR (KBr)
tmax : 2925, 1731, 1436, 1373, 1241,
1079, 1034, 965 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 7.40–7.35 (m, 2H), 7.34–
7.30 (m, 1H), 7.28–7.24 (m, 2H), 6.87 (dt, J = 9.8, 3.9 Hz, 1H), 6.67 (d, J = 15.8
Hz, 1H), 6.13 (dd, J = 15.8, 7.9 Hz, 1H), 6.04 (d, J = 9.8 Hz, 1H), 5.67–5.62 (m,
1H), 4.58–4.52 (m, 1H), 2.43–2.37 (m, 2H), 2.24–2.17 (m, 1H), 2.09 (s, 3H); 13
C
NMR (75 MHz, CDCl3): d 169.9, 164.0, 144.5, 135.5, 133.3, 128.5, 126.6, 126.4,
121.5, 74.1, 70.7, 39.8, 29.4, 21.2; Mass (ESI-MS) m/z: 309 [M+Na]+; HRMS (ESI)
[M+Na]+ m/z calcd for C17H18O4Na 309.1102, found 309.1098. Compound 8:
Yellow liquid; ½a D32
ꢁ
: +3.2 (c 0.4, CHCl3); IR (neat)
tmax: 3454, 2929, 2856, 1720,
1643, 1201, 1070 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 7.25–7.15 (m, 4H), 7.13–
7.07 (m, 1H), 6.44 (d, J = 15.3 Hz, 1H), 6.36–6.26 (m, 1H), 6.10 (dd, J = 15.3,
6.4 Hz, 1H), 5.78 (d, J = 11.5 Hz, 1H), 4.60–4.55 (m, 1H), 3.99–3.91 (m, 1H), 3.60
(s, 3H), 2.78–2.63 (m, 2H), 1.73–1.58 (m, 2H), 0.87 (s, 9H), 0.05 (s, 6H); 13C
NMR (75 MHz, CDCl3): d 166.9, 146.6, 136.6, 131.5, 129.8, 128.5, 127.5, 126.4,
120.8, 72.3, 67.9, 51.0, 43.3, 36.8, 25.8, 18.1, -4.4, -5.1; Mass (ESI-MS)
m/z:413 [M+Na]+; HRMS (ESI): calcd C22H34O4NaSi 413.2124, found
In conclusion, a concise total synthesis of (+)-(6R,20S)-crypto-
caryalactone and (ꢀ)-(6S,20S)-epi cryptocaryalactone has been
accomplished. The key reactions involved for the synthesis of com-
pounds 2 and 3 are asymmetric acetate aldol reaction, Evans acetal
intramolecular oxa-Michael reaction, Still–Gennari reaction and
acid catalyzed lactonisation.
413.2111.Compound 3. Yellowish liquid;
(neat) max: 3038, 3005, 2948, 2922, 1725, 1498, 1429, 1371,1240, 1072,
1030, 970 816, 750 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.43–7.23 (m, 5H), 6.87
½ ꢁ = ꢀ74.8 (c 0.4, CHCl3); IR
a 2D8
t
;
(dt, J = 9.0, 5.2 Hz, 1H), 6.70 (d, J = 15.8 Hz, 1H), 6.13 (dd, J = 15.8, 7.5 Hz, 1H),
6.03 (d, J = 10.5 Hz, 1H), 5.67 (q, J = 14.3, 6.7 Hz, 1H), 4.58–4.46 (m, 1H),

J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 2496–2499
2499
2.46–2.30 (m, 2H), 2.11–1.94 (m, 2H), 2.09 (s, 3H); 13C NMR (75 MHz, CDCl3): d
170.1, 163.8, 144.6, 135.7, 133.9, 128.6, 128.2, 126.6, 126.0, 121.4, 74.6, 71.2,
39.6, 29.3, 21.2; Mass (ESI-MS) m/z: 309 [M+Na]+; HRMS (ESI) [M+Na]+calcd for
4.80 (m, 1H), 3.72 (dd, J = 17.5, 3.0 Hz, 1H), 3.41 (dd, J = 17.5, 8.4 Hz, 1H), 3.38
(d, J = 10.9 Hz, 1H), 3.25 (dd, J = 13.0, 3.7 Hz, 1H), 3.05 (dd, J = 13.0, 10.5 Hz,
1H), 2.89 (d, J = 11.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 201.3, 172.3, 136.3,
130.5, 129.8, 129.3, 128.8, 128.4, 127.7, 127.2, 126.4, 125.7, 68.5, 68.2, 45.6,
36.7, 32.0; Mass (ESI-MS) m/z: 406 [M+Na]+; HRMS (ESI) [M+Na]+ calcd for
C
17H18O4Na 309.1102, found 309.1098. Compound 10. Yellow liquid.
= ꢀ132.7 (c 1.0, CHCl3); IR (neat): tmax 3447, 3025, 2924, 1689, 1346,
1261, 1159, 1042, 749 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.41–7.17 (m, 10H),
6.67 (d, J = 16.0 Hz, 1H), 6.26 (dd, J = 16.0, 5.8 Hz, 1H), 5.43–5.34 (m, 1H), 4.89–
½ ꢁ
a 2D8
;
C21H21NO2NaS2 406.0911, found 406.0913.