Total synthesis of stagonolide B

Article abstract of DOI:10.1016/j.tetlet.2011.12.119

Asymmetric total synthesis of nonenolide stagonolide-B has been presented in this Letter. The main highlight of our synthetic strategy is the application of hydroxynitrile lyase (ParsHNL) mediated asymmetric synthesis of cyanohydrin, Sharpless asymmetric dihydroxylation, cross metathesis (CM) reaction, stereoselective Keck allylation reaction and Yamaguchi macrolactonization at a late stage enables us to achieve the synthesis of the target molecule in an efficient way.

Full text of DOI:10.1016/j.tetlet.2011.12.119

Tetrahedron Letters 53 (2012) 1186–1189
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of stagonolide B
⇑
Tapas Das, Tridib Mahapatra, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric total synthesis of nonenolide stagonolide-B has been presented in this Letter. The main high-
light of our synthetic strategy is the application of hydroxynitrile lyase (ParsHNL) mediated asymmetric
synthesis of cyanohydrin, Sharpless asymmetric dihydroxylation, cross metathesis (CM) reaction, stere-
oselective Keck allylation reaction and Yamaguchi macrolactonization at a late stage enables us to
achieve the synthesis of the target molecule in an efficient way.
Received 10 December 2011
Revised 26 December 2011
Accepted 27 December 2011
Available online 3 January 2012
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Small ring macrolide
Enzymatic hydrocynation
Asymmetric allylation
Cross metathesis
Macrolactonization
Stagonolides are a class of naturally occurring nonenolides iso-
lated from a fungal pathogen Stagonospora cirsii. These small ring
macrolides possess interesting biological activities (mainly phyto-
toxic). In a preliminary study, it was observed that S. cirsii is capa-
ble of producing phytotoxic metabolites, because isolated culture
filtrates demonstrated phytotoxic activity. Five new nonenolides,
named stagonolides B–F, were isolated and characterized using
spectroscopic methods.1 Further four nonenolides were isolated la-
ter on and characterized by spectroscopy. Three were new com-
pounds named stagonolides G–I, and the fourth was identified as
modiolide A, previously isolated from Paraphaeosphaeria sp., a fun-
gus separated from the horse mussel (Fig. 1).2 In our continuous ef-
fort toward the synthetic studies of the small ring macrolides, we
have already reported the total synthesis of stagonolide C,3 stagon-
olide D & G,4 stagonolide-E,5 chloriolide,6 and achaetolide.7 The
main highlight of our previous synthetic strategy was chemoenzy-
matic kinetic resolution coupled with Mitsunobu inversion and
chemoenzymatic dynamic kinetic resolution to access some valu-
able chiral secondary alcohol intermediates. These intermediates
are then employed successively to gain access of more advanced
intermediates which have close resemblance to the target mole-
cule. In the final step of synthesis we often apply RCM reaction
by Grubbs catalyst as well as several macrolactonization protocols.
The success of our synthetic strategy depends on the optimization
of RCM method and macrolactonization protocol.
successful application of RCM (ring closing metathesis) reaction at
late stage with Grubbs olefin metathesis catalyst.10 In this Letter
we would like to report our synthetic strategies for the asymmetric
total synthesis of stagonolide-B by the successful application of
Yamaguchi macrolactonization. Our retrosynthetic analysis of stag-
onolide-B is presented in Scheme 1.
We have planned to adopt a Yamaguchi macrolactonization11 at
the penultimate step from the properly substituted seco acid (2),
which in turn can be accessed from intermediate 3 by asymmetric
catalytic allylation reaction.12 Cross metathesis reaction was
thought to be applied to construct the C6–C7 olefinic unsaturation
from the intermediate 4.13 The intermediate 4 can be achieved from
(Z)-ester 5 by asymmetric dihydroxylation reaction.14 Ester 5 can be
prepared from aldehyde 7, synthesized by ParsHNL catalyzed hydro-
cyanation reaction (Scheme 2).
We have started our synthetic journey from the commercially
available n-butanal. Asymmetric hydrocyanation reaction with Pru-
nus armeniaca hydroxynitrile lyase (ParsHNL) and HCN in DIPE
(diisopropyl ether) solvent afforded the corresponding (R)-cyanohy-
drin in a 92% yield (ee = 96%).15 The enzymatic hydrocyanation with
hydroxynitrile lyase is a well documented strategy for the asymmet-
ric synthesis of cyanohydrins, and we have explored the methodol-
ogy extensively in our group by using a (R)-HNL (hydroxynitrile lyase
from Prunus armeniaca) from Himalayan apricot (Prunus armeniaca,
Shakarpara cultivar).16 The reaction is very efficient in terms of
chemical yield as well as excellent enantioselection in the product
cyanohydrins. The secondary hydroxyl group in (R)-6 is protected
as its TBDPS ether by treatment with TBDPS-Cl and imidazole fol-
lowed by treatment with DIBAL-H at À78 °C afforded the aldehyde
7 in a 72% yield (two steps). cis-Selective HWE (Horner–Wads-
worth–Emmons) olefination reaction by Ando protocol17 yielded
Till today three asymmetric syntheses of stagonolide-B are re-
ported in the literature.8,9 All the synthetic strategies involve the
⇑
Corresponding author. Tel: +91 3222 283328; fax: +91 3222 282252.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.119

T. Das et al. / Tetrahedron Letters 53 (2012) 1186–1189
1187
OH
OH
OH
O
O
OH
OH
O
O
O
O
O
O
OH
HO
O
O
O
nPr
OH
OH
Stagonolide-C
Stagonolide-D
Stagonolide-B
Modiolide-B
Z; Modiolide-A
E; Stagonolide-I
O
O
OH
O
OH
OH
O
O
O
O
Stagonolide-H
HO
O
OH
O
Stagonolide-F
Stagonolide-E
Stagonolide G
Figure 1. Naturally occurring stagonolides.
OH
OP
7
asymmetric
allylation
6
OHC
OH
OH
O
macrolactonisation
O
O
5
1
P'O
O
HO
O
HO2C
3
nPr
O
nPr
2
nPr
P = MOM; P' = TBDPS
Stagonolide-B; 1
CM
asymmetric
dihydroxylation
EtO2C
P'O
O
O
P'O
CHO
nPr
P'O
7
nPr
nPr
5
4
Scheme 1. Retrosynthetic analysis of stagonolide-B.
the Z-olefin 5 in an 82% yield.18 Asymmetric dihydroxylation reac-
tion of olefin 5 with ADmix-b afforded the diol 8 in a 79% yield.19
The diol 8 is protected as its acetonide 9, by treatment with 2,2-
DMP (2,2-dimethoxypropane) in an 87% yield. The ester functional-
ity in compound 9 was reduced with DIBAL-H to afford aldehyde 10
in an 82% yield. Wittig olefination with triphenylphosphoniumm-
ethyl iodide in the presence of LHMDS at 0 °C afforded the olefin 4
in an 80% yield. Cross metathesis reaction with freshly distilled acro-
lein in the presence of Hoveyda–Grubbs metathesis catalyst (HG-II,
5 mol %) afforded the unsaturated aldehyde (exclusively E) 3 in an
85% yield.20 Catalytic asymmetric allylation under Keck condition
with allyltributylstanane and (R)-BINOL afforded compound 11 in
a 76% yield.21 The secondary hydroxyl group is protected as its
MOM ether22 by treatment with MOM-Cl and DIPEA to yield 12 in
an 88% yield. Regioselective hydroboration with BH3/SMe2 yielded
the alcohol 13 (72%). PDC oxidation23 of alcohol 13 afforded the car-
boxylic acid 14 in a 78% yield. Deprotection of the TBDPS group is
achieved by treating 14 with TBAF to afford the seco acid 2 in an
88% yield. The crude seco acid is subjected to macrolactonization
reaction under Yamaguchi condition to afford the cyclized lactone
product 15 in a 62% yield.24 Finally deprotection of the MOM group
is achieved by treating compound 15 in presence of PTSA in DCM to
afford stagonolide-B (1) in an 80% yield (overall yield = 4.2% from n-
butanal; Scheme 2). The spectral characteristic values (1H & 13C
NMR) of our synthesized stagonolide-B match perfectly with the
natural stagonolide-B.2,7
In conclusion an efficient chemoenzymatic asymmetric synthe-
sis of the target molecule stagonolide-B has been accomplished in a
linear way. The main highlights of our synthetic strategy involves
the application of hydroxynitrile lyase mediated asymmetric
cyanohydrin synthesis, asymmetric dihydroxylation reaction,
stereoselective cross metathesis reaction, catalytic asymmetric
allylation, and finally macrolactonization of properly functional-
ized hydroxyl acids yields the target molecule in an efficient way.
Acknowledgments
We are thankful to CSIR (New Delhi, India; Grant No: 01-2109/
07/EMR-II) and DBT (New Delhi, India; Grant No: BT/PR13830/PID/
06/568/2010) for financial support and DST (New Delhi, India) for
NMR facility at our institute. Two of the authors (T.D. and T.M.) are
thankful to CSIR for senior research fellowship.
Supplementary data
Supplementary data (1H and 13C NMR spectra for all new com-
pounds are available) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.119.

1188
T. Das et al. / Tetrahedron Letters 53 (2012) 1186–1189
O
EtO2C
PO
EtO2C
PO
OH
OH
a
b
c
d
CN
nPr
HO
CHO
PO
nPr
n-butanal
7
6
5
nPr
nPr
8
OHC
O
O
OHC
PO
EtO2C
PO
O
O
O
e
f
g
h
PO
PO
O
O
O
nPr
3
nPr
nPr
9
nPr
10
4
OH
OMOM
OMOM
PO
O
O
j
i
l
O
O
k
PO
PO
O
O
11
12
13
nPr
OH
OH
nPr
nPr
OMOM
OMOM
O
O
O
OH
OH
O
m
n
PO
O
HO2C
O
14
nPr
O
nPr
O
nPr
15
Stagonolide-B; 1
N
Cl
N
MeS
MeS
P = TBDPS (tertbutyldiphenylsilyl)
Ru
O
Cl
Hoveyda-Grubbs catalyst (HG-II)
Scheme 2. Asymmetric synthesis of stagonolide-B. Reagents and conditions: (a) ParsHNL (Prunus armeniaca hydroxynitrile lyase), HCN, DIPE, citrate buffer (pH = 4.0), 6 h,
92%; (b) (i) Imidazole, TBDPS-Cl, DMAP (cat), 12 h, 88%; (ii) DIBAL-H, DCM, À78 °C, 82%; (c) (PhO)2POCH2CO2Et, NaH, 0 °C, 82%; (d) AD mix-b, t-BuOH–H2O (4:1), MeSO2NH2;
79%; (e) 2,2-DMP, CSA, 87%; (f) DIBAL-H, DCM, À78 °C, 82%; (g) LHMDS, PH3P+MeI, 0 °C, 1 h, 80%; (h) HG-II (5 mol %), acrolein, reflux, DCM, 6 h, 85%; (i) (R)-BINOL, Ti(OiPr)4,
allyl tributylstanane, DCM, À20 °C, 80 h, 76%; (j) MOM-Cl, DIPEA, rt, 12 h, 88%; (k) BH3:Me2S, THF, NaOH, H2O2, 3 h, 72%; (l) PDC, DMF, 6 h, 78%; (m) (i) TBAF, THF, rt, 3 h, 88%;
(ii) 2,4,6-trichlorobenzoylchloride, DIPEA (diisopropylethyl amine), DMAP, toluene 60 °C, 24 h, 62%; (n) PTSA, DCM, 12 h, 80%.
Oitra, S.; Murga, J.; Carda, M.; Marco, J. A. Org. Lett. 2010, 12, 5752; (j) Kumar, C.
N. S. S.; Ravinder, M.; Kumar, S. N.; Rao, V. J. Synthesis 2011, 451–458; (k)
References and notes
Chandrasekhar, S.; Balaji, S. V.; Rajesj, G. Tetrahedron Lett. 2010, 51, 5164; (l)
1. Evidente, A.; Capasso, R.; Andolfi, A.; Vurro, M.; Chiara Zonno, M. Nat. Toxins
Rao, K. S.; Chatttapadhyay, A.; Ghosh, S. Synlett 2010, 3078; (m) Sabitha, G.;
1999, 6, 183.
Srinivas, R.; Yadav, J. S. Synthesis 2011, 3343.
2. (a) Evidente, A.; Cimmino, A.; Berestetskiy, A.; Mitina, G.; Andolfi, A.; Motta, A.
10. Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc 1996, 118, 100.
J. Nat. Prod. 2008, 71, 31; (b) Evidente, A.; Cimmino, A.; Berestetskiy, A.; Andolfi,
11. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
A.; Motta, A. J. Nat. Prod. 2008, 71, 1897; (c) Greve, H.; Schupp, P. J.; Eguereva,
1979, 52, 1989.
E.; Kehraus, S.; Konig, G. M. J. Nat. Prod. 2008, 71, 1651.
12. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467.
3. Jana, N.; Mahapatra, T.; Nanda, S. Tetrahedron: Asymmetry 2009, 20, 2622.
13. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
4. Mahapatra, T.; Das, T.; Nanda, S. Bull. Chem. Soc. Jpn. 2011, 84, 511.
122, 8168.
5. Das, T.; Nanda, S. Tetrahedron Lett. 2012, 53, 256.
6. Das, T.; Jana, N.; Nanda, S. Tetrahedron Lett. 2010, 51, 2644.
14. Tietze, L. F.; Eicher, T.; Diederichsen, U.; Speicher, A. In Reactions and Syntheses;
Wiley-VCH: Weinheim, 2007; p 211.
7. Das, T.; Bhuniya, R.; Nanda, S. Tetrahedron: Asymmetry 2010, 21, 2206.
15. (a)Bhunya, R.; Jana, N.; Das, T.; Nanda, S. Syn Lett, 2009, 1237–1240. (b)
8. (a) Srihari, P.; Kumaraswamy, B.; Somaiah, R.; Yadav, J. S. Synthesis 2010, 1039;
Bhunya, R.; Mahapatra, T.; Nanda, S. Tetrahedron : Asymmetry, 2009, 20, 1526–
(b) Prabhakar, P.; Rajaram, S.; Kumar Reddy, D.; Shekar, V.; Venkateswarlu, Y.
1530.
Tetrahedron: Asymmetry 2010, 21, 216; (c) Giri, A. G.; Mondal, M. A.; Puranik, V.
(R)-2-Hydroxypentanenitrile (6): To a solution of n-butanal (7.2 g, 0.1 mol) in
G.; Ramana, C. V. Org. Biomol. Chem 2010, 8, 398.
DIPE (60 ml), a solution of ParsHNL (300 IU/10 mmol of aldehyde, approxi-
9. For total synthesis of stagonolides and related molecules from other groups
mately 10 ml of crude enzyme solution) was added and the resulting mixture
see: (a) Srihari, P.; Maheswara Rao, G.; Srinivasa Rao, R.; Yadav, J. S. Synthesis
was stirred vigorously until an emulsion was formed. The pH of the enzyme
2010, 2407; (b) Mohapatra, D. K.; Somaiah, R.; Rao, M. M.; Caijo, F.; Mauduit,
solution was previously adjusted to 4.0 with 10% citric acid solution. Freshly
M.; Yadav, J. S. Synlett 2010, 1223; (c) Mohapatra, D. K.; Dash, U.; Naidu, R. P.;
prepared HCN in DIPE (2 equiv) was added to it, and the temperature of the
Yadav, J. S. Synlett 2009, 2129; (d) Srihari, P.; Kumaraswamy, B.; Maheswara
solution was kept at 10 °C. After completion of the reaction it was extracted
Rao, G.; Yadav, J. S. Tetrahedron: Asymmetry 2010, 21, 106; (e) Perepogu, A. K.;
thoroughly with ether several times and the organic layer was dried (Na2SO4).
Raman, D.; Murty, U. S. N.; Rao, V. J. Biorg. Chem. 2009, 37, 46; (f) Giri, A. G.;
Evaporation of the solvent yielded the crude cyanohydrin which was purified
Mondal, M. A.; Puranik, V. G.; Ramana, C. V. Org. Biomol. Chem. 2010, 8, 398; (g)
by chromatography.
Srihari, P.; Kumaraswamy, B.; Shankar, P.; Ravishashidhar, V.; Yadav, J. S.
Preparation of HCN in DIPE: NaCN (10 g) and citric acid (0.1 g) were dissolved in
Tetrahedron Lett. 2010, 51, 6174; (h) Srihari, P.; Kumaraswamy, B.; Bhunia, D.
water (100 mL). The solution was cooled in an ice/water bath and extracted
C.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 2903; (i) Angulo-Pachon, C. A.; Diaz-
with DIPE (50 mL), while acidifying with 33% HCl until pH 5.5. The water layer,

T. Das et al. / Tetrahedron Letters 53 (2012) 1186–1189
1189
as
which contained a suspension of NaCl, was extracted twice with DIPE (25 mL).
chromatography (pet ether/ethyl acetate: 1/10) affords aldehyde
yellow oil with 85% yield.
3
a
The combined DIPE layers were stored in a dark bottle. The above procedure
must be performed in a well ventilated fume hood with proper glass ware and
hand wares (gloves).
21. Keck, G. E.; Truong, A. P. Org. Lett., 2005, 7, 2149.
(R,E)-1-((4S,5S)-5-((R)-1-(tert-butyldiphenylsilyloxy)
butyl)-2,2-dimethyl-1,3-
16. The enantiomeric excess (ee) of the hydrocyanation reaction was determined
with the help of chiral HPLC analysis of the corresponding benzoate derivative
(Chiralpak AD-H; hexane: isopropanol = 19:1; flow rate 0.9 ml/min;
tmajor = 6.8 min; tminor = 7.2 min).
dioxolan-4-yl)hexa-1,5-dien-3-ol (compound 11):
A
mixture of (R)-BINOL
(60.3 mg, 0.21 mmol), 1 M Ti(O-i-pr)4 in DCM (0.21 ml, 0.21 mmol), and oven-
dried powdered 4-A sieves in DCM was heated at reflux for 1 h. The red-brown
mixture was cooled to room temperature and aldehyde 3 (1 g, 2.1 mmol) was
added. After being stirred for 10 min, the contents were cooled to À78 °C, and
allyltri-n-butylstannane (772.4 mg, 2.33 mmol) was added. The reaction was
stirred for 10 min and then placed in a preset reaction chamber at À20 °C for
80 h. Saturated NaHCO3 (0.7 ml) was added, and the contents were stirred for
1 h and then poured over Na2SO4 and filtered through celite. The crude mixture
was purified by flash chromatography (pet ether/ethyl acetate: 5:1) afforded
the compound 11 with 76% yield. Formation of a minor diastereomer was
indicated in TLC and was separated by chromatography (de = 19:1).
17. Ando, K. J. Org. Chem. 1997, 62, 1934.
18. (R,Z)-ethyl 4-(tert-butyldiphenylsilyloxy)hept-2-enoate (compound 5): To
a
solution of Ethyl (diphenylphosphono) acetate (3.7 g, 11.76 mmol) in THF
(45 ml) was added NaH (60%) ((470.4 mg, 11.76 mmol) at 0 °C; 15 min later,
aldehyde 7 (4.0 g, 11.76 mmol) in THF (10 ml) was added, and the resulting
mixture was gradually warmed to the room temperature over 1.2 h. After that
time water was added to it, extracted with ethyl acetate and brine. The organic
extract was dried over MgSO4 and evaporated to yielded the crude olefin (Z/
E = 95:5) which was separated by flash chromatography to afford ester 5 in 82%
yield.
22. Stork, G.; Takahashi, T. J. Am. Chem. Soc. 1977, 99, 1275.
23. Chen, J.; Li, Y.; Cao, X. Tetrahedron: Asymmetry 2006, 17, 933.
19. (2R,3S,4R)-ethyl
4-(tert-butyldiphenylsilyloxy)-2,3-dihydroxyheptanoate
(11.6 g) were
24. (3aR,4S,9R,11aS,E)-9-(methoxymethoxy)-2,2-dimethyl-4-propyl-4,5,8,9-
(compound 8): t-BuOH (29 ml), H2O (29 ml) and AD-mix
b
tetrahydrocyclodeca[d][1,3]dioxol-6(3aH,7H,11aH)-one
(compound
15):
mixed and the mixture was stirred for 15 min. Methanesulfonamide (1.1 g)
was then added and the stirring was continued for a further 15 min. Ester
compound 5 (3.5 g, 8.53 mmol) was then added and the slurry was stirred
vigorously at 20 °C for 24 h, sodium sulfite (15 g) was added and stirring was
continued for further 1 h. The reaction mixture was extracted with EtOAc, the
organic layer was dried over Na2SO4 and evaporated in vacuo. The diol was
purified by flash chromatography (1:3; EtOAc–hexane) to afford (79%) of the
diol 8 as a single isolable product.
Compound 14 (125 mg, 0.21 mmol) was taken in dry THF (2 ml). TBAF (1 M
in THF, 0.42 ml) was added to it, and the reaction mixture was stirred for 3 h at
room temperature. After that time, THF was evaporated and water (4 ml) was
added to it. The reaction mixture was extracted with EtOAc (50 ml). The
organic layer was washed with NaHCO3 and brine, dried over Na2SO4, purified
by flash chromatography (5:1; hexane–EtOAc) to afford 40 mg hydroxy acid in
a 50% yield.
To a solution of hydroxy acid (40 mg, 0.11 mmol) in dry toluene (10 ml) were
added 2,4,6-trichlorobenzoyl chloride (0.4 ml, 2.3 mmol) and diisopropyl ethyl
amine (0.8 ml) at 23 °C. The resulting mixture was stirred for 15 h at the same
temperature. The solution was diluted by the addition of dry tolune (10 ml)
and was added by syringe pump slowly to a solution of DMAP (240 mg,
2.76 mmol) in dry tolune (200 ml) at 60 °C over 10 h. The reaction was stirred
for an additional 24 h at the same temperature and quenched by adding
saturated aqueous NH4Cl solution, extracted by ethyl acetate, dried,
concentrated, and purified by column chromatography (pet ether/ethyl
acetate: 20/1) afforded the lactone 15 in a 62% yield.
20. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc., 2000,
122, 8168.
(E)-3-((4S,5S)-5-((R)-1-(tert-butyldiphenylsilyloxy)butyl)-2,2-dimethyl-1,3-
dioxolan-4-yl) acrylaldehyde (compound 3): A flame-dried round-bottom flask
was charged with olefin 4 (2.5 g 5.7 mmol), freshly distilled acrolein (0.578 ml,
8.66 mmol) and dicholoromethane (25 ml). Hoveyda–Grubbs catalyst (HG-II,
5 mol %) was subsequently added as a solid, producing a light green solution
which was refluxed for 6 h. The mixture was then concentrated in vacuo to a
dark brown oil. Purification of this residue on silica gel by flash