Stereoselective synthesis of the C9-C19 lactone-dipropionate fragment of calyculin C

Article abstract of DOI:10.1016/j.tetlet.2004.09.012

A highly diastereoselective synthesis of the title fragment of calyculin C has been developed based on an internal asymmetric induction between a chiral aldehyde and Z-crotyl trifluorosilane.

Full text of DOI:10.1016/j.tetlet.2004.09.012

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8245–8248
Stereoselective synthesis of the C9–C19
lactone-dipropionate fragment of calyculin C
Kaisa Karisalmi and Ari M. P. Koskinen*
Laboratory of Organic Chemistry, Helsinki University of Technology, PO Box 6100, FIN-02015 HUT, Finland
Received 23 June 2004; revised 24 August 2004; accepted 2 September 2004
Available online 23 September 2004
Abstract—A highly diastereoselective synthesis of the title fragment of calyculin C has been developed based on an internal asym-
metric induction between a chiral aldehyde and Z-crotyl trifluorosilane.
Ó 2004 Elsevier Ltd. All rights reserved.
Calyculins form a class of highly cytotoxic metabolites
from the marine sponge Discodermia calyx originally
isolated by Fusetani and co-workers.1 They have proven
to be strong serine/threonine protein phosphatase inhibi-
tors2 and based on this property, calyculins might be
potential anti-cancer agents.3
Several different syntheses of this fragment have been
published with varying strategies.4 The most challenging
part in the synthesis of this C9–C20 fragment is the anti,
anti,anti-stereotetrad, which can be reached either by
linear4e,d or by convergent4a–c approaches. However,
the syntheses published so far have many weaknesses
(too many steps, poor diastereoselectivity, or need for
inversion of stereocenters). Therefore, improved routes
to this fragment are still needed.
The C9–C19 lactone-dipropionate fragment 5 of calycu-
lin C (boxed in Fig. 1) contains 8 out of the total of
16 stereocenters and is thereby a key substructure of this
sponge metabolite.
We have recently published a convergent approach
toward the C9–C19 fragment5 of calyculin C, which
unfortunately led to a wrong diastereomer. In this com-
munication we would like to present a short, highly dia-
stereo-, and enantioselective linear synthesis of the
lactone-dipropionate fragment 5 of calyculin C.
OH
O
O
MeO
Me2N
N
H
Our synthesis of C9–C19 fragment of calyculin C is based
on a short and highly enantioselective synthesis of the
key intermediate 15 followed by two asymmetric crotyl-
ation reactions (Scheme 1). Armstrong and co-workers
have used a similar strategy in their synthesis of the
C9–C25 fragment of calyculin6 but in the last crotylation
step they obtained only a disappointing 1:1.3 diastereo-
selection. We wished to improve this selectivity by using
Z-crotyl trifluorosilane as the crotylation reagent in the
second crotylation step.7
OH
N
O
(HO)2PO2
CN
OH
O
OH
OH
OMe
Calyculin C
Figure 1.
The synthesis of the key intermediate 1 is shown in
Scheme 2.5 The first crotylation reaction was realized
with the crotyl borane derived from E-butene and (+)-
MeOB(Ipc)2 (Scheme 3).8 The reaction yielded a 6:1
mixture of two diastereomeric anti-homoallylic alcohols,
the major product8 being isolated from the mixture by
Keywords: Aldol reactions; Crotylation; Diastereoselectivity; Natural
products; Stereoselective synthesis.
*
Corresponding author. Tel.: +358 9451 2526; fax: +358 9451 2538;
e-mail: ari.koskinen@hut.fi
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.012

8246
K. Karisalmi, A. M. P. Koskinen / Tetrahedron Letters 45 (2004) 8245–8248
MEMO
asymmetric
crotylation
asymmetric
crotylation
MEMO
MEMO
O
O
O
O
O
O
O
O
O
OMe
OH OMe
2
OMe
1
5
Scheme 1.
O
O
O
OH
O
O
O
O
c
b
a
O
BnO
O
BnO
O
BnO
O
O
O
OH
MEMO
MEMO
HO
O
g, h
f
e
d
O
O
O
O
BnO
BnO
BnO
O
O
O
O
1
OMe
OMe
OMe
OMe
Scheme 2. Reagents and conditions: (a) i. LDA, THF, À78°C, 1h, ii. PhCH2OCH2CH2CHO, À78°C, 1h, 75%; (b) NEt3, MsCl, CH2Cl2, 0°C, 3.5h,
85%; (c) OsO4, (DHQD)2PHAL, K3Fe(CN)6, K2CO3, NaHCO3, MeSO2NH2, t-BuOH/H2O, 0°C, 17h, 78% quantitative, 91% ee after
crystallization; (d) Ag2O, MeI, Et2O, reflux, 21h, 62%; (e) L-Selectride, THF, À78°C, 10min, 58–69%; (f) DIPEA, MEMCl, CH2Cl2, reflux, 44h, 73–
87%; (g) Pd(OH)2/C, H2, EtOH, rt, 0.5h, 91% quantitative; (h) TPAP, NMO, CH2Cl2, rt, 0.5h, 65–75%.
MEMO
MEMO
MEMO
b
O
a
O
O
O
O
O
O
O
OMe
1
OH OMe
3
OH OMe
2
c
MEMO
MEMO
d
O
O
O
O
O
O
OMe
OH OH OMe
5
4
Scheme 3. Reagents and conditions: (a) i. the crotyl reagent was prepared from (+)-IpcBOMe and E-butene in THF at À78°C, ii. BF3ÆOEt, the
˚
aldehyde 1, À78°C, 1h, iii. ethanolamine; (b) i. O3, CH2Cl2, À78°C, ii. triphenylphosphine, rt, 3h; (c) i. aldehyde 3, 4A MS, CH2Cl2, rt, 0.5h, ii. 0°C,
DIPEA, Z-crotyl trifluorosilane, 4h; (d) 2-methoxypropene, pyridinium p-toluenesulfonate (PPTS) (cat.), CH2Cl2, rt, 0.5h.
simple flash chromatography. The homoallylic alcohol 2
was then treated with O3 to furnish the corresponding b-
hydroxy aldehyde 39 (Scheme 3). The final crotylation
was performed with Z-crotyl trifluorosilane.10,11 The
existing hydroxyl group directs the stereochemistry to-
ward the anti,anti,anti-stereotetrad without any external
source of chirality.7 This crotylation produced a single
Ha
Hc
1H: J (Ha-Hb) = 11.1, J (Hb-Hc) = 9.8
13C chemical shifts:
R1
acetonide acetal 97.1 ppm
O
acetonide methyls 30.1 and 19.6 ppm
Me
O
R2
Hb
1
diastereomer 412 based on the H NMR spectrum of
Figure 2.
the crude product. Finally the diol 4 was converted to
the corresponding ketal 5.13
propose that the stereochemistry of the stereotetrads in
4 and 5 has to be anti,anti,anti.
1
The H and 13C NMR analyses revealed the relative
stereochemistry of the ketal ring (Fig. 2). The 13C spec-
trum provided strong evidence for a syn-1,3-diol rela-
tionship14 while the couplings in the 1H NMR
spectrum and NOESY correlations revealed the axial–
axial relationship of the protons in the ketal ring.
These preliminary results of the synthesis of the chal-
lenging anti,anti,anti-dipropionate structure of calyculin
C are very important in the field of natural product
total synthesis. The anti,anti,anti-stereochemistry was
achieved in only three steps with satisfactory diastereo-
selectivity. The crotylation methodology (Z-crotyl trifluo-
rosilane) recently developed by Chemler and Roush7
The spectroscopic evidence together with the known
facts about the two crotylation reactions6,7 lead us to

K. Karisalmi, A. M. P. Koskinen / Tetrahedron Letters 45 (2004) 8245–8248
8247
33.2, 44.5, 45.1, 59.0, 68.4, 71.6, 72.4, 79.0, 82.5, 83.4, 97.2,
115.9, 140.1, 180.1; HRMS m/z calcd for C18H32O7 + Na:
383.2046; found: 383.2051(M+Na+).
proved to be a useful reaction in the synthesis of the
anti,anti,anti-stereotetrad. Scaling up and optimization
of the reactions are currently under way.
9. Compound 3: olefin 2 (15mg, 0.042mmol, 100mol%) was
dissolved in CH2Cl2 (3mL) in a flame-dried flask, the
mixture was cooled to À78°C, and ozone was bubbled
through the mixture until a blue color persisted (2min).
Then O2 was bubbled through the mixture until the color
disappeared, after which triphenylphosphine (16mg,
0.062mmol, 150mol%) was added, the cooling bath was
removed and the mixture was stirred at rt for 3h. The
solvent was evaporated in vacuo and the crude product
was purified by mini-flash (15% to >30% IPA–hexane) and
9mg (60%) of the b-hydroxyaldehyde was obtained. Rf
0.06 (15% IPA–hexane, PMA stain); [a]D À3.1 (c
Acknowledgements
Financial support from the Finnish Academy is grate-
fully acknowledged.
References and notes
1. Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.
J. Am. Chem. Soc. 1986, 108, 2780.
0.75, CHCl3); IR (film) 3436, 1772, 1722cmÀ1
; dH
2. Sheppeck, J. E., II; Gauss, C.-M.; Chamberlin, A. R.
Bioorg. Med. Chem. 1997, 5, 1739.
(400MHz, CDCl3): 1.16 (3H, d, O@CHCHCH3R,
J = 7.2), 1.26 (6H, s, RCOCCH3CH3COO), 1.69 (1H,
dd, OHCHCHaHbCHOMe, J = 14.6, 7.8), 1.93 (1H, ddd,
OHCHCHaHbCHOMe, J = 14.6, 4.1, 2.0), 2.47–2.52 (1H,
m, O@CHCHCH3R), 3.38 (3H, s, CH3OCH2CH2R),
3.51–3.58 (2H, m, CH3OCH2R), 3.55 (3H, s, CH3OR),
3.60–3.67 (2H, m, CH3OCH2CHaHbR, OH), 3.72–3.76
(1H, m, CH3OCH2CHaHbR), 3.85 (1H, td, CH2CHO-
MeR2, J = 7.8, 4.1), 4.02 (1H, d, RCHOMEM, J = 4.2),
4.08–4.12 (1H, m, O@CHCHCH3CHOHR), 4.54 (1H, dd,
R2CHOCOR, J = 7.8, 4.2), 4.68 (1H, d, OCHaHbO,
J = 6.5), 4.78 (1H, d, OCHaHbO, J = 6.5), 9.77 (1H, d,
RHC@O, J = 2.0); dC (100MHz, CDCl3): 10.5, 18.8, 23.3,
33.5, 45.1, 52.0, 59.0, 59.3, 68.3, 70.7, 71.7, 78.8, 82.6, 83.2,
97.2, 179.9, 205.0; HRMS m/z calcd for C17H30O8 + Na:
385.1838; found: 385.1806 (M+Na+).
3. Bridges, A. J. Chemtracts-Org. Chem. 1995, 8, 73.
4. (a) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem.
Soc. 1992, 114, 9434; (b) Yokokawa, F.; Hamada, Y.;
Shiori, T. Chem. Commun. 1996, 871; (c) Smith, A. B.;
Friestad, G. K.; Duan, J. J.-W.; Barbosa, J.; Hull, K. G.;
Iwashima, M.; Qui, Y.; Spoors, P. G.; Bertonesque, E.;
Salvatore, B. A. J. Org. Chem. 1998, 63, 7596; (d) Ogawa,
A. K.; Armstrong, R. W. J. Am. Chem. Soc. 1998, 120,
12435; (e) Tanimoto, N.; Gerritz, S. W.; Sawabe, A.;
Noda, T.; Filla, S. A.; Masamune, S. Angew. Chem., Int.
Ed. 1994, 33, 673.
5. Karisalmi, K.; Koskinen, A. M. P. Synthesis 2004, 1331.
6. Scarlato, G.; DeMattei, J. A.; Chong, L. S.; Ogawa, A. K.;
Lin, M. R.; Armstrong, R. W. J. Org. Chem. 1996, 61,
6139.
7. Chemler, S. R.; Roush, W. R. J. Org. Chem. 2003, 68,
1319.
8. Compound 2: t-BuOK (42mg, 0.37mmol, 150mol%) was
suspended in dry THF (1.5mL) in a flame-dried flask
under Ar and this mixture was cooled to À78°C. Excess E-
butene (condensed in another flask) was added via
cannula, followed by n-BuLi (0.185mL, c = 2.0M,
0.37mmol, 150mol%). The yellow mixture was stirred at
À45°C for 15min, then re-cooled to À78°C and (Ipc)2-
BOMe (158mg, 0.5mmol, 200mol%) in 1mL of THF was
added via cannula (the yellow color disappeared). This
mixture was stirred at À78°C for 1/2h, then BF3ÆOEt
(41mL, 0.325mmol, 130mol%) and aldehyde 1 (75mg,
0.25mmol, 100mol%) were added. After 1h the reaction
mixture was concentrated and re-dissolved in 3mL of dry
Et2O, cooled in an ice-bath and 15mL of ethanolamine
was added. The mixture was stirred at rt over night,
filtered through Celite, and purified by flash chromato-
graphy (60% EtOAc–hexane). 19mg (21%) of a 6:1
mixture of two diastereomers was isolated and the major
diastereomer (12mg) was obtained in pure form after
second mini-flash purification (15% IPA–hexane). Rf 0.2
(60% EtOAc–hexane, PMA stain); [a]D +4.2 (c 1.0,
CHCl3); IR (film) 3502, 1776cmÀ1; dH (400MHz, CDCl3):
1.04 (3H, d, CH2@CHCHCH3R, J = 6.9), 1.24 (6H, s,
RCOCCH3CH3COO), 1.56 (1H, ddd, OHCHCHaHb-
CHOMe, J = 14.7, 9.8, 6.9), 1.81 (1H, ddd, OHCH-
CHaHbCHOMe, J = 14.7, 4.5, 1.8), 2.17–2.26 (1H, m,
CH2@CHCHCH3R), 3.38 (3H, s, CH3OCH2CH2R), 3.51–
3.58 (2H, m, CH3OCH2R), 3.51 (3H, s, CH3OR), 3.65–
3.81 (4H, m, CHOHCH2CHOMe + CH3OCH2CH2R),
4.02 (1H, d, RCHOMEM, J = 4.2), 4.49 (1H, dd,
R2CHOCOR, J = 4.2, 7.8), 4.68 (1H, d, OCHaHbO,
J = 6.7), 4.78 (1H, d, OCHaHbO, J = 6.7), 5.06–5.12
(2H, m, CH2@CH), 5.75–5.84 (1H, ddd, CH2@CHR,
J = 16.8, 11.0, 8.1); dC (100MHz, CDCl3): 16.0, 18.9, 23.3,
10. Kira, M.; Hino, T.; Sakurai, H. Tetrahedron Lett. 1989,
30, 1099.
11. Personal communication with Professor Sherry Chemler.
12. Compound 4: b-hydroxy aldehyde 3 (3mg, 8.26mmol,
100mol%) was dissolved in CH2Cl2 (0.6mL) in a pear-
shaped flame-dried flask under Ar together with 10mg of
˚
crushed and activated 4A molecular sieves. The mixture
was stirred at rt for 25min, then cooled in an ice-bath,
after which DIPEA (4mL, 0.025mmol, 300mol%) and Z-
crotyl trifluorosilane (4mL, 0.026mmol, 320mol%) were
added. After 4h stirring at 0°C the reaction was complete
and it was quenched with satd NH4Cl. The mixture was
extracted 3 EtOAc, the combined organic phase were
*
dried over Na2SO4, the drying agent was filtered, and the
solvent evaporated in vacuo. After purification with mini-
flash (15% IPA–hexane) 1–2mg of the desired anti,
anti,anti aldol product was obtained. Rf 0.55 (30% IPA–
hexane, PMA stain); [a]D +4.6 (c 0.13, CHCl3); IR (film)
3468, 1773cmÀ1; dH (400MHz, CDCl3): 0.85 (3H, d,
CHOHCHCH3CHOH, J = 6.8), 1.12 (3H, d, CH2@
CHCHCH3R, J = 7.0), 1.25 (6H, s, RCOCCH3CH3COO),
1.55–1.63 (1H, m, OHCHCHaHbCHOMe), 1.63–1.73 (1H,
m, CHOHCHCH3CHOH), 1.93 (1H, d, OHCHCHaHb-
CHOMe, J = 12.2), 2.43–2.47 (1H, m, CH2@
CHCHCH3R), 3.38 (3H, s, CH3OCH2CH2R), 3.38–3.40
(1H, m, CHCH3CHOHCHCH3), 3.53–3.57 (2H, m,
CH3OCH2R), 3.55 (3H, s, CH3OR), 3.66–3.77 (2H, m,
CH3OCH2CH2R), 3.83 (1H, td, CH2CHOMeR2, J = 7.8,
4.4), 3.96 (1H, t, CHCH3CHOHCH2, J = 7.8), 4.00 (1H,
d, RCHOMEM, J = 4.4), 4.54 (1H, dd, R2CHOCOR,
J = 7.8, 4.4), 4.67 (1H, d, OCHaHbO, J = 6.5), 4.84 (1H, d,
OCHaHbO, J = 6.5), 5.06–5.12 (2H, m, CH2@CHR), 5.90
(1H, ddd, CH2@CHR, J = 17.4, 10.4, 8.2); dC (100MHz,
CDCl3): 12.8, 17.8, 18.9, 23.4, 29.7, 40.7, 41.8, 45.1, 59.1,
59.4, 68.5, 71.8, 77.2, 78.1, 79.4, 82.7, 83.5, 97.4, 115.8,
139.0, 180.0; HRMS m/z calcd for C21H38O8 + Na:
441.2464; found: 441.2449 (M+Na+).

8248
K. Karisalmi, A. M. P. Koskinen / Tetrahedron Letters 45 (2004) 8245–8248
13. Compound 5: diol 4 (1.5mg, 3.54mmol, 100mol%) was
dissolved in 0.2mL of CH2Cl2 and 2-methoxypropene
(2mL, 17.9mmol, 500mol%) followed by pyridinium p-
toluenesulfonate (PPTS) (cat.) were added. After 0.5h the
reaction was quenched with satd NaHCO3, the mixture
(3H, s, CH3OCH2CH2R), 3.41–3.44 (1H, m, CH3O-
CHaHbCH2OR), 3.42 (3H, s, CH3OR), 3.53–3.56
(2H, m, CH3OCHaHbCHaHbOR), 3.68 (1H, ddd,
CH2CHOMeR2, J = 8.2, 5.7, 2.5), 3.69–3.74 (1H, m,
CH3OCH2CHaHbOR), 3.76 (1H, dd, CHCH3CHORCH2,
J = 11.1, 9.5), 4.14 (1H, d, RCHOMEM, J = 3.8),
4.54 (1H, dd, R2CHOCOR, J = 8.2, 3.8), 4.72 (1H, d,
OCHaHbO, J = 7.0), 4.79 (1H, d, OCHaHbO, J = 7.0),
4.97–5.03 (2H, m, CH2@CHR), 5.84 (1H, ddd,
CH2@CHR, J = 17.2, 10.3, 9.2); dC (100MHz,
CDCl3): 11.8, 18.0, 18.9, 19.6, 23.1, 30.1, 31.4,
35.7, 39.6, 45.5, 57.8, 59.1, 68.4, 69.5, 71.6, 77.2, 77.7,
82.0, 83.8, 97.1, 97.4, 114.9, 139.7, 180.3; HRMS m/z
calcd for C24H42O8 + Na: 481.2777; found: 481.2782
(M+Na+).
was extracted 3 EtOAc, the combined organic phase
*
were dried over Na2SO4, the drying agent was filtered,
and the solvent evaporated. The crude product was
not purified before analysis. Rf 0.5 (30% IPA–hexane,
PMA stain); IR (film) 1776cmÀ1
;
dH (400MHz,
CDCl3): 0.76 (3H, d, CHORCHCH3CHOR, J = 6.6),
1.05 (3H, d, CH2@CHCHCH3R, J = 6.9), 1.26 (6H, s,
RCOCCH3CH3COO), 1.30 (3H, s, OC(CH3CH3)O), 1.40
(3H, s, OC(CH3CH3)O), 1.37–1.40 (1H, m, OCH-
CHCH3CHO), 1.63 (1H, ddd, ORCHCHaHbCHOMe,
J = 14.9, 9.5, 2.5), 2.05 (1H, ddd, ORCHCHaHbCHOMe,
J = 14.9, 5.7, 1.5), 2.39–2.45 (1H, m, CH2@CHCHCH3R),
3.38 (1H, dd, CH2@CHCHCH3CHOR, J = 9.8, 2.1), 3.39
14. (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett.
1990, 31, 945; (b) Evans, D. A.; Rieger, D. L.; Gage, J. R.
Tetrahedron Lett. 1990, 31, 7099.