The reaction mechanism of spirocylization and stereoselectivity studies for the calyculin C16-C25 fragment

Article abstract of DOI:10.1002/ejoc.200500206

The mechanism of the double intramolecular hetero-Michael addition, a key reaction in the planned synthesis of the natural product calyculin C, has been studied by NMR. The cyclization follows Baldwin's rules and proceeds first through a six-membered ring

Full text of DOI:10.1002/ejoc.200500206

FULL PAPER
The Reaction Mechanism of Spirocylization and Stereoselectivity Studies for
the Calyculin C16–C25 Fragment
Vesa Rauhala,[a] Kalle Nättinen,[b] Kari Rissanen,[c] and Ari M. P. Koskinen*[a]
Keywords: Michael addition / Cyclization
The mechanism of the double intramolecular hetero-Michael
addition, a key reaction in the planned synthesis of the natu-
ral product calyculin C, has been studied by NMR. The cycli-
zation follows Baldwin’s rules and proceeds first through a
six-membered ring closure (6-endo-dig), followed by a five-
membered ring cyclization (5-exo-trig).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
The 1,6-dioxaspiro[4.5]decane ring system is a ubiquitous
structure occurring in nearly 100 natural products.[1] It is
noteworthy that the configurations of the stereogenic car-
bon atoms in most of these structures are dictated by
double anomeric effects, placing the oxygen in the oxolane
ring axial with respect to the oxane ring (Figure 1).[2] Be-
cause of the wide occurrence of such motifs, a rapid and
reliable route to the spirocyclic structure is highly desirable.
This was of special interest to us because of our ongoing
efforts[3] towards the total synthesis of calyculin C, a potent
protein phosphatase inhibitor.[4] We have recently commu-
nicated[3j] a rapid route to such spikoketals based on the
use of the double intramolecular hetero-Michael addition
(DIHMA) technique.[5] In this paper we report a stereose-
lective approach to the spiroketal model fragment of calycu-
lin C[6] as well as our results on the study of the reaction
mechanism.
Utilising the DIHMA approach for the construction of
the spiroketal required the ynone 12 as the penultimate cyc-
lization precursor (Scheme 1). This should be available
through a nucleophilic addition of the alkyne 7 onto the
Weinreb amide 11, this in turn being available by the Evans
aldol methodology from propionyloxazolidinone and (ben-
zyloxy)propanal. The alkyne 7 was prepared through a Sey-
ferth–Gilbert-type homologation[7] of lactol 4, available
enantioselectively in two steps from the enoate 1.
Figure 1. Spiroketal fragment of calyculin C.
Results
The stereoselective synthesis of alkyne 7 is shown in
Scheme 2. Sharpless asymmetric dihydroxylation of enoate
1 resulted in spontaneous lactonization and gave the desired
single enantiomer of lactone 2 in 82% yield and with
75% ee, which was increased to Ͼ97% ee by recrystalli-
sation (Figure 2).[8] Lactonization was also tested with AD-
mix α, which gave 63–67% ee. The free alcohol was pro-
tected as the benzyl ether (benzyl 2,2,2-trichloroacetimid-
ate, CF3SO3H, 91%).[9] Reduction of 3 with DIBAL-H af-
forded lactol 4 in 90% yield after purification. Original Sey-
ferth–Gilbert-type homologation requires harsher reaction
conditions than the widely used Ohira’s reagent 5 to trans-
form an aldehyde into the corresponding alkyne.[7,10] The
aldehyde surrogate 4 was transformed into alkyne 6 in 61%
[a] Laboratory of Organic Chemistry, Helsinki University of Tech-
nology,
P.O. Box 6100, 02015 HUT, Finland
E-mail: Ari.Koskinen@hut.fi
[b] VTT Processes,
P.O. Box 1607, 33101 VTT
E-mail: kalle.nattinen@vtt.fi
[c] Nanoscience Center, Department of Chemistry, University of
Jyväskylä,
P.O. Box 35, 40014 Jyväskylä, Finland
E-mail: kari.rissanen@jyu.fi
Eur. J. Org. Chem. 2005, 4119–4126
DOI: 10.1002/ejoc.200500206
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. Rauhala, K. Nättinen, K. Rissanen, A. M. P. Koskinen
FULL PAPER
Scheme 1. Retrosynthetic analysis for the spiroketal fragment 14.
recycled yield, and the primary hydroxy group was pro- lidinone (8) and 3-(benzyloxy)propionaldehyde to give the
tected with TBS to give the alkyne 7 (89%) ready for coup- desired 9 in 80% yield and 99% ee (Scheme 3). Synthesis of
ling.[3j]
the Weinreb amide 10 from a different propionyloxazolidi-
none has been reported previously in the literature.[12] In
our case conversion of 9 into 10 succeeded in 89% yield,
and TBS protection (TBSOTf, 2,6-lutidine, 89%) gave the
desired coupling partner 11.
Scheme 3. Reagents: i) 8, Bu2BOTf, Et3N, CH2Cl2, T Ͻ 2 °C; then
BnOCH2CH2CHO, –77 °C. ii) MeOMeNH·HCl, AlMe3, THF,
0 °C. iii) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C.
Scheme 2. Reagents: i) DHQ-PYR, K3Fe(CN)6, K2CO3, H2O/
tBuOH (1:1), OsO4, 0 °C. ii) CH2Cl2/cyclohexane (1:3), benzyl
2,2,2-trichloroacetimidate, CF3SO3H, 35 °C. iii) DIBAL-H,
PhMe, –78 °C. iv) 5, K2CO3, MeOH, 36 °C. v) TBSOTf, 2,6-luti-
dine, CH2Cl2, 0 °C.
Weinreb–Nahm-type coupling of alkyne 7 and the Wein-
reb amide 11 produced alkynone 12 in 62% yield
(Scheme 4).[13] The yield was lower than previously re-
ported, due to some unreacted starting materials remaining.
The stepwise DIHMA[5] method afforded the spirocycle as
a single enantiomer (86%). A DPFGSE-NOE experiment
between C(23)H and C(22)H/C(16)H2 ensured the correct
conformation (calyculin numbering; see also Figure 3).
Stereoselective reduction of spiroketal 13 with -Selectride
afforded the desired axial diastereomer 14 in 68% yield.[14]
The reaction mechanism for the cyclisation of the steri-
cally highly hindered 1,6-dioxaspiro[4.5]decane spiroketal
remained open (Scheme 5). In order to shed light on this
matter, we conducted the spirocyclization, catalysed by
CSA, in the NMR tube in deuterated methanol. The reac-
tion was monitored at regular intervals. The TBS protection
Figure 2. Crystal structure of lactone 2.
The enantiopure Weinreb amide 11 fragment was pre- is cleaved from the primary alcohol group first (as evi-
pared as previously reported, by an Evans syn-selective al- denced by the immediate disappearance of the signals at
dol reaction[11] between (4R)-4-benzyl-3-propionyl-2-oxazo- about 4.0 and 3.8 ppm, Figure 4). After 0.5 h the first trace
4120
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Eur. J. Org. Chem. 2005, 4119–4126

Study of a Key Reaction in the Planned Synthesis of Calyculin C
FULL PAPER
Scheme 4. Reagents: i) BuLi, 7, then 11, THF –78 °C. ii) CSA, MeOH, then pTsOH, PhH, room temp. iii) -Selectride, THF, –78 °C.
of the six-membered ring in H(22) at 4.2 ppm can be seen,
and signals around 3.95 and 3.75 ppm start to appear
(CH2-16), disappearing later and being replaced by the sig-
nals of the final spirocycle at ca. 3.75 and 3.80 ppm. In
accordance with Baldwin’s rules for ring-closure,[15] the 6-
endo-dig cyclisation is clearly favourable, whereas the 5-exo-
dig process is less favoured.[16]
The suggested reaction path is therefore path a
Figure 3. Double-pulsed field-gradient spin-echo (DPFGSE) NOE
(Scheme 5). However, it is impossible to distinguish whether
experiment.
Scheme 5. Possible reaction pathways.
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V. Rauhala, K. Nättinen, K. Rissanen, A. M. P. Koskinen
FULL PAPER
Figure 4. Reaction T(0) + 8 min to T(0) +16 h 14 min.
chromatography. Optical rotations were measured at 20 °C on a
Perkin–Elmer 343 polarimeter. IR spectra were measured with a
Perkin–Elmer Spectrum One instrument. Elemental analyses were
performed with a Perkin–Elmer 2400 CHN Elemental Analyzer.
HRMS spectra were measured with Jeol JMS-DX 303 and Micro-
mass LCT instruments. NMR spectra were measured with a Bruker
AMX 400 (1H 400.13 MHz, 13C 100.61 MHz). The single-crystal
X-ray diffraction for lactone 2 was done with a Nonius KappaCCD
the spirocyclization occurs directly from A1 or through the
intermediates A2 and C.
Conclusions
We have presented a stereoselective route to obtain the
spiroketal fragment of calyculin C. We also succeeded in
discovering that cyclization mechanism follows Baldwin’s
rules and proceeds first through a six-membered ring (6-
endo-dig) followed by a five-membered ring cyclization (5-
exo-trig). Application in the total synthesis of calyculin C is
under investigation.
diffractometer with graphite-monochromatized Mo-Kα (λ
=
0.71073 Å) radiation. Collect software was used in the measure-
ment and DENZO-SMN[17] in the processing of the data. The
structure was solved and refined by full-matrix least-squares on
F2 with the WinGX software package utilizing SHELXS97 and
SHELXL97 modules.[18–20] Hydrogen atoms were refined by a ri-
ding model. Absorption correction was not performed for the com-
pound.
Experimental Section
CCDC-255366 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, UK; Fax: +44-1223/336-033; E-mail: deposit@ccdc.cam-
.ac.uk].
General: All reactions were conducted under positive pressure of
argon. THF was distilled prior to use from sodium-benzophenone,
MeOH from Mg(OMe)2 and toluene from sodium. Other solvents
were p.a. grade. Melting points, determined on a Gallenkamp
MFB-595 melting point apparatus, were not corrected. TLC was
conducted on Merck 0.25 mm silica gel 60 F plates and samples
were viewed with UV light, anisaldehyde, PMA and ninhydrin
staining. Flash chromatography was performed with Merck silica
gel 60 (230–400 mesh) as a stationary phase. HPLC was performed
with a Waters 501 pump, a Waters 486 tuneable absorbance detec-
tor and a Waters 746 data module with the following columns:
Shandon Hypersil Silica Column with Waters Guard-PakTM pre-
column fitted with ResolveTM silica inserts for normal phase
chromatography and Daicel Chiralcel OD 25 cm×0.46 cm with
(R)-4-Hydroxy-3,3-dimethyl-4,5-dihydro-3H-furan-2-one (2): DHQ-
PYR (0.264 g, 0.30 mmol, 1.0 mol%), K3Fe(CN)6 (29.6 g,
90 mmol, 300 mol%) and K2CO3 (12.4 g, 90 mmol, 300 mol%)
were dissolved in a mixture of H2O (140 mL) and tBuOH
(140 mL), followed by OsO4 (1.5 mL of 2.5 wt.-% in 2-methylpro-
pan-2-ol). The reaction mixture was cooled to 0 °C, and compound
1 (3.85 g, 30 mmol, 100 mol%) in a mixture of H2O (10 mL) and
tBuOH (10 mL) was added. This mixture was stirred overnight at
0 °C and after 18.5 h was quenched by addition of Na2SO3 (37.9
g) and H2O (50 mL). The phases were separated, the aqueous phase
Daicel Chiracel OD
5 cm×0.46 cm precolumn for chiral
4122
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 4119–4126

Study of a Key Reaction in the Planned Synthesis of Calyculin C
FULL PAPER
was extracted five times with EtOAc (50 mL), and the combined
organic phases were then extracted once with brine (50 mL) and
dried with MgSO4. The crude product was filtered through a silica
pad with 50% EtOAc/hexane and pure EtOAc. The product was
purified by crystallizing it twice from a mixture of pentane (10 mL)
and EtOAc (2.8 mL) to afford 2 (3.2 g, 82%, 97.5% ee) as white
needle-like crystals; m.p. 59–60 °C; Rf (50% EtOAc/hexane, UV/
dimethyl
(1-diazo-2-oxopropyl)phosphonate
(5)
(0.264 g,
1.332 mmol, 200 mol%) and K2CO3 (0.184 g, 1.332 mmol,
200 mol%) were added. The reaction mixture was warmed to 33 °C
and allowed to stir for five days, during which more phosphonate
5 (0.066 g, 0.33 mmol, 50 mol%) and K2CO3 (0.046 g, 0.33 mmol,
50 mol%) were added (five times, once a day). The blue-green reac-
tion mixture was evaporated to dryness and dissolved in EtOAc
permanganate) = 0.20; Rt (GC, cyclodextrin beta, inj. temp. and H2O (1:1 mixture, 20 mL). The phases were separated and the
270 °C, vel. 28, 100–220 °C 4 °C·min–1, 220 °C 30 min, det. temp.
aqueous one was extracted four times with EtOAc (10 mL) and
once with brine (10 mL) and dried with MgSO4. Crude 6 was puri-
270 °C) = 20.61 min. [α]2D0 = –5.1 (c = 1.0; CHCl3); 1H NMR
(400 MHz, CDCl3): δ = 1.24 (s, 6 H, CH3), 2.51 (d, J = 4.4 Hz, 1 fied by step gradient column chromatography (10%, 15%, 20% and
H, OH), 4.13 (dd, J = 3.2, 10.0 Hz, 1 H, CHaHb), 4.20 (ddd, J =
3.2, 4.4, 4.4 Hz, 1 H, CH), 4.45 (dd, J = 4.4, 10.0 Hz, 1 H,
25% EtOAc/hexane in 250 mL portions), affording a slightly yellow
oil (0.088 g, 61%). Rf (50% EtOAc/Hex, UV/anisaldehyde) = 0.48;
CHaHb) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.2, 22.7, 43.6, Rt (GC, cyclodextrin beta, inj. temp. 270 °C, vel. 28, 100–220 °C
71.9, 75.5, 181.2 ppm. IR (film): ν
= 1760, 3459 cm–1. C6H10O3
4 °C·min–1, 220 °C 30 min, det. temp. 270 °C) = 27.63 min. [α]2D0
=
˜
max
1
(130.1418): C 55.37, H 7.74; found C 55.13, H, 7.83.
0.58 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.26 (s, 3
H, CH3), 1.30 (s, 3 H, CH3), 1.88 (dd, J = 7.4, 5.3 Hz, 1 H, OH),
2.19 (s, 1 H, C(CH3)2CCH), 3.40 (dd, J = 6.6, 3.8 Hz, 1 H,
CHOBn), 3.77 (ddd, J = 11.8, 6.6, 5.3 Hz, 1 H, CHaHbOH), 3.92
(R)-4-(Benzyloxy)-3,3-dimethyl-4,5-dihydro-3H-furan-2-one
(3):
Lactone 2 (0.105 g, 0.807 mmol, 100 mol%) was dissolved in a mix-
ture of CH2Cl2 (2 mL) and cyclohexane (6 mL). Benzyl 2,2,2-trich-
loroacetimidate (0.360 mL, 1.94 mmol, 240 mol%) and CF3SO3H
(17 µL, 0.192 mmol, 24 mol%) were added, and the reaction mix-
ture was heated to 35 °C. White, solid trichloroacetamide appeared
in the yellow reaction mixture, and was filtered off after three hours
and washed through twice with cyclohexane (5 mL). The combined
organic phases were extracted with sat. NaHCO3 (2×10 mL) and
once with brine (10 mL) and were dried with MgSO4. Product 3
was purified by step gradient column chromatography (10%, 15%
and 25% MTBE/hexane in 100 mL portions) affording the light
yellow oil 0.163 g (91%). Rf (50% EtOAc/hexane, UV/PMA) =
(ddd, J = 11.8, 7.4, 3.8 Hz, 1 H, CHaHbOH), 4.72 (d, JAB
=
11.5 Hz, 1 H, CHaHbPh), 4.78 (d, JAB = 11.5 Hz, 1 H, CHaHbPh),
7.30–7.39 (m, 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
24.7, 26.7, 34.7, 62.6, 69.8, 74.7, 85.6, 89.7, 127.8, 127.8, 128.5,
138.3 ppm. IR (film): ν
= 1029, 1102, 3295, 3436 cm–1. HRMS
˜
max
(TOF MS EI+) calcd. for C14H18O2NaSi 241.1204; found 241.1206.
[(R)-2-(Benzyloxy)-3,3-dimethylpent-4-ynyloxy]-tert-butyldimethyl-
silane (7): The alcohol 6 (0.073 g, 0.334 mmol, 100 mol%) was dis-
solved in dry CH2Cl2 (4 mL) and cooled to 0 °C. 2,6-Lutidine
(0.156 mL, 1.34 mmol, 400 mol %) was added, and the reaction
mixture was allowed to stir for 1 h 13 min, after which TBSOTf
(0.154 mL, 0.67 mmol, 200 mol%) was added. After 20 min the re-
action was quenched with sat. K2CO3 (2 mL). The mixture was
partitioned between water and Et2O (20 mL, 1:1) and the phases
were separated. The aqueous phase was extracted four times with
Et2O (10 mL) and the combined organic phase was dried with
MgSO4. Crude 7 was purified by column chromatography (10%
EtOAc/hexane), affording pure product (0.099 g, 89%) as a slightly
yellow oil. Rf (50% EtOAc/hexane, UV/PMA) = 0.72. [α]2D0 = –1.1
0.46. [α]2D0 = –5.3 (c = 1.0; CHCl3). H NMR (400 MHz, CDCl3):
1
δ = 1.25 (s, 3 H, CH3), 1.28 (s, 3 H, CH3), 3.90 (dd, J = 4.0, 5.2 Hz,
1 H, CH), 4.15 (dd, J = 4.0, 10.0 Hz, 1 H, CHaHb), 4.31 (dd, J =
5.2, 10.0 Hz, 1 H, CHaHb), 4.58 (d, JAB = = 12.1 Hz, 2 H, CH2Ph),
7.29–7.38 (m, 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
17.9, 23.4, 42.9, 68.9, 72.1, 81.9, 127.5, 128.0, 128.5, 137.4,
180.6 ppm. IR (film): ν
= 1773 cm–1. HRMS (TOF MS EI+)
˜
max
calcd. for C13H16O3Na: 243.0997; found 243.0979.
1
(4R)-4-(Benzyloxy)-3,3-dimethyl-tetrahydrofuran-2-ol (4): Lactone 3
(0.342 g, 1.55 mmol, 100 mol%) in toluene (15 mL) was cooled to –
78 °C. DIBAL-H (1  in toluene, 2.64 mL, 2.64 mmol, 170 mol%)
was added over 10 min. After 11 min, the reaction was quenched
by addition of MeOH (1.0 mL) and allowed to warm up to room
temp. The solution was partitioned between HCl (1 , 25 mL) and
EtOAc (25 mL) and was stirred for an hour. The phases were sepa-
rated and the aqueous phase was extracted three times with EtOAc
(15 mL). The combined organic phases were washed once with sat.
NaHCO3 (10 mL) and brine (10 mL) and were dried with MgSO4.
The crude product was purified by step gradient column
chromatography (15%, 20%, 25%, and 30% EtOAc/hexane in
200 mL portions), affording pure 4 (0.310 g, 90%) as a slightly yel-
low oil. Rf (50% EtOAc/hexane, UV/PMA) = 0.41. 1H NMR
(400 MHz, CDCl3): δ = 1.00 (s, 3 H, CH3), 1.23 (s, 3 H, CH3), 3.56
(d, J = 12.0 Hz, 1 H, CHOH), 3.61 (d, J = 3.8 Hz, 1 H, CHOBn),
4.05 (dd, J = 10.2, 3.8 Hz, 1 H, CHaHb), 4.22 (d, J = 10.2 Hz, 1
H, CHaHb), 4.43 (d, JAB = 11.9 Hz, 1 H, CHaHbPh), 4.64 (d, JAB
= 11.9 Hz, 1 H, CHaHbPh), 4.80 (d, J = 11.0 Hz, 1 H, CHOH),
7.29–7.38 (m, 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
17.2, 24.0, 46.5, 70.9, 72.1, 85.3, 105.2, 127.6, 127.9, 128.5,
(c = 1.0; CHCl3). H NMR (400 MHz, CDCl3): δ = 0.07 (s, 3 H,
CH3), 0.08 (s, 3 H, CH3), 0.92 (s, 9 H, C(CH3)3), 1.20 (s, 3 H,
CH3), 1.27 (s, 3 H, CH3), 2.14 (s, 1 H, C(CH3)2CCH), 3.36 (dd, J
= 7.3, 2.7 Hz, 1 H, CH), 3.80 (dd, J = 10.8, 7.3 Hz, 1 H, OCHaHb),
4.10 (dd, J = 10.8, 2.7 Hz, 1 H, OCHaHb), 4.65 (d, JAB = =
11.5 Hz, 1 H, PhCHaHb), 4.92 (d, JAB = 11.5 Hz, 1 H, PhCHaHb),
7.24–7.38 (m, 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = –
5.4, –5.3, 18.2, 24.4, 25.9, 27.0, 34.7, 65.4, 69.1, 74.5, 86.1, 90.0,
127.3, 127.8, 128.1, 139.0 ppm. IR (film): ν
= 837, 1069, 1256,
˜
max
3309 cm–1. HRMS (TOF MS EI+) calcd. for C20H32O2NaSi
355.2069; found 355.2079.
(R)-4-Benzyl-3-[(2R,3S)-5-(benzyloxy)-3-hydroxy-2-methyl-
pentanoyl]-2-oxazolidinone (9): (R)-4-Benzyl-3-propionyl-2-oxazoli-
dinone (8) (1.0 g, 4.3 mmol, 100 mol %) was dissolved in dry
CH2Cl2 (20 mL) and cooled to 0 °C, after which dibutylboron trifl-
ate (1  in CH2Cl2, 6.75 mL, 6.8 mmol, 157 mol %) was added
dropwise, with the internal temperature being maintained under
2 °C. The colour in the reaction mixture changed to brown, but
when Et3N (1.02 mL, 7.3 mmol, 171 mol%) was added (T Յ 2 °C)
it turned from transparent to yellow and shortly afterwards to bur-
gundy. After 40 minutes the reaction mixture was cooled to –77 °C
and 3-(benzyloxy)propionaldehyde (1.02 g, 6.2 mmol, 144 mol%),
dissolved in dry CH2Cl2 (2 mL), was added slowly (35 min), with
the internal temperature being kept stable. Stirring was continued
for a further 3 h at –77 °C and then for 30 min at 0 °C. Phosphate
137.4 ppm. IR (film): ν
= 1725, 3435 cm–1. HRMS (TOF MS
˜
max
EI+) calcd. for C13H18O3Na: 245.1154; found 245.1171.
(R)-2-(Benzyloxy)-3,3-dimethylpent-4-yn-1-ol (6): Lactol 4 (0.148 g,
0.666 mmol, 100 mol%) was dissolved in dry MeOH (7 mL), and
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buffer (10 mL, pH 7.0) and methanol (8 mL) were added, and the
mixture was cooled to –10 °C, before slow (15 min) addition of
H2O2 (30%) and MeOH (1:1, 20 mL). The mixture was then stirred
for 30 min at 0 °C, after which the organic solvents were evapo-
rated, Et2O was added and reaction mixture was cooled to –10 °C.
Sat. aqueous Na2S2O3 (17 mL) was added slowly (20 min) and the
phases were separated. The aqueous phase was extracted three
times with Et2O (10 mL) and the combined organic phases were
washed once with sat. NaHCO3 (12 mL) and brine (8 mL) and
dried with MgSO4. Crude 9 was purified by gradient flash column
chromatography (15%, 20% and 25% EtOAc/Hex in 200 mL por-
tions), affording pure 9 (1.36 g, 80%, 99% ee). Rf (50% EtOAc/
Hex, UV/acid-PMA) = 0.31. [α]2D0 = –44.7 (c = 1.0; CHCl3); Rt
(HPLC, Daicel, ChiracelR OD, 250 mm, 4.6 mm, 20% IPA/Hex,
The phases were separated and the organic phase was washed five
times with aq. H3PO4 (0.5 ) and once with H2O (20 mL). The
combined organic phases were dried with MgSO4. Crude 11 was
purified by step gradient column chromatography (10%, 15%, 20%
and 25% EtOAc/hexane in 500 mL portions), affording pure 11
(0.512 g, 89%) as a yellow oil. Rf (50% EtOAc/Hex, UV/PMA) =
1
0.45. [α]2D0 = +2.3 (c = 1.0; CHCl3). H NMR (400 MHz, CDCl3):
δ = 0.04 (s, 3 H, CH3), 0.06 (s, 3 H, CH3), 0.88 (s, 9 H, C(CH3)3),
1.13 (d, J = 7.0 Hz, 3 H, CH3CH), 1.82–1.88 (m, 2 H, CH(OTBS)
CH2), 2.98 (br.s, 1 H, CHMe), 3.13 (s, 3 H, CH3N), 3.49–3.62 (m,
2 H, CH2OBn), 3.59 (s, 3 H, NOCH3), 4.04 (td, J = 7.8, 5.0 Hz, 1
H, CHOTBS), 4.45 (d, JAB = 12.1 Hz, 1 H, OCHaHbPh), 4.49 (d,
JAB = 12.1 Hz, 1 H, OCHaHbPh), 7.23–7.34 (m, 5 H, ArH). 13C
NMR (100 MHz, CDCl3): δ = –4.5, –4.4, 14.4, 18.1, 25.9, 32.1,
35.4, 41.3, 61.2, 66.5, 71.4, 72.9, 127.4, 127.7, 128.3, 138.6,
1
254 nm, 1.0 mL·min–1) = 17.52 min. H NMR (400 MHz, CDCl3):
δ = 1.28 (d, J = 7.0 Hz, 3 H, CH3), 1.71–1.80 (m, 1 H, CH(OH)
176.3 ppm. IR (film): ν
= 836, 1103, 1663 cm–1. HRMS (EI+)
˜
max
CHaHb), 1.83–1.92 (m, 1 H, CH(OH)CHaHb), 2.77 (dd, J = 13.4, calcd. for C21H37NO4NaSi 418.2390; found 418.2397.
9.5 Hz, 1 H, PhCHaHb), 3.25 (dd, J = 13.4, 3.3 Hz, 1 H,
(3S,4R,9R)-1,9-Bis(benzyloxy)-3,10-bis(tert-butylsilyloxy)-4,8,8-tri-
PhCHaHb), 3.34 (d, J = 2.4 Hz, 1 H, OH), 3.63–3.73 (m, 2 H,
methyldec-6-yn-5-one (12): The alkyne 7 (0.057 g, 0.172 mmol,
CH2OBn), 3.82 (dq, J = 7.0, 3.8 Hz, 1 H, CHMe), 4.13–4.20 (m,
200 mol%) was dissolved in dry THF (1.7 mL) and cooled to –
OCH2CH(Bn)N, 3 H, CHOH), 4.51 (s, 2 H, OCH2Ph), 4.67 (m, 1
78 °C. BuLi (2.25 , 84 µL, 0.189 mmol, 220 mol%) was added,
and the reaction mixture was allowed to stir for 1 h, after which the
H, OCH2CH(Bn)N), 7.19–7.34 (m, 10 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 11.1, 33.7, 37.7, 42.5, 55.2, 66.1, 68.3, 70.4,
Weinreb amide 11 (0.034 g, 0.086 mmol, 100 mol%) in dry THF
73.2, 127.3, 127.6, 128.4, 128.4, 128.9, 129.4, 135.1, 138.0, 153.0,
(0.9 mL) was added. After 55 min, the reaction mixture was al-
176.6 ppm. IR (film): ν
= 1111, 1694, 1780, 3480 cm–1. HRMS
˜
max
lowed to warm up to room temp. and after another 3 h 21 min it
was quenched with H2O (5 mL). Et2O (10 mL) and brine (5 mL)
were added and the phases were separated. The aqueous phase was
extracted three times with Et2O (10 mL) and the combined organic
(EI+) calcd. for C23H27NO5Na 420.1787; found 420.1815.
(2R,3S)-5-(Benzyloxy)-3-hydroxy-N-methoxy-N,2-dimethylpentana-
mide (10): A 25 mL two-necked flask was charged with N,O-di-
methylhydroxylamine hydrochloride (0.54 g, 5.5 mmol, 220 mol%) phases were dried with MgSO4. The crude product was purified by
and THF (4 mL). The suspension was cooled to –10 °C in a NaCl/ step gradient chromatography (5%, 10% and 15% EtOAc/hexane
ice bath and AlMe3 (2  in Hexane, 2.64 mL, 5.3 mmol, 210 mol%) in 15 mL portions), affording 12 (0.035 g, 62%) as a yellow oil. Rf
was added over 5 min. After 12 min, the cooling bath was removed
and the reaction mixture was allowed to stir for 1 h at room temp.,
after which it was cooled again to –10 °C. Oxazolidinone 9 (1.0 g,
2.5 mmol, 100 mol %) dissolved in a mixture (4:5) of CH2Cl2
(2.9 mL) and THF (4 mL) was slowly added. The mixture was
stirred for 3 h 15 min at 0 °C and at room temp. for another 1 h
30 min, after which it was poured into a pre-cooled 0 °C mixture
(1:1, 32 mL) of HCl [0.5 ] and CH2Cl2. This was stirred for 2 h
at 0 °C and the phases were separated. The aqueous phase was
extracted three times with CH2Cl2 (30 mL) and the combined or-
ganic phases were washed once with H2O (40 mL) and dried with
MgSO4. The crude product was purified by step gradient column
chromatography (30%, 40%, 50% EtOAc/hexane and pure EtOAc
in 700 mL fractions), affording 10 as a yellow oil (0.617 g, 89%).
Rf (50% EtOAc/Hex, UV/PMA) = 0.16. [α]2D0 = –1.8 (c = 0.5;
CHCl3) (ref.[12] [α]2D6 = –11.1 (c = 1.65; CHCl3)). NMR (400 MHz,
(50% EtOAc/Hex, UV/PMA) = 0.73. [α]2D0 = –1.1 (c = 1.0; CHCl3).
1H NMR (400 MHz, CDCl3): δ = 0.01 (s, 3 H, CH3Si), 0.03 (s, 3
H, CH3Si), 0.06 (s, 3 H, CH3Si), 0.07 (s, 3 H, CH3Si), 0.84 (s, 9 H,
C(CH3)3), 0.91 (s, 9 H, C(CH3)3), 1.13 (d, J = 6.9 Hz, 3 H,
CH3CH), 1.24 (s, 3 H, CH3C), 1.28 (s, 3 H, CH3C), 1.77–1.92 (m,
J = 14.0, 6.4 Hz, 2 H, CH(OTBS)CH2), 2.57 (qd, J = 6.9, 3.8 Hz,
1 H, CHMe), 3.38 (dd, J = 7.1, 3.0 Hz, 1 H, CHOBn), 3.49 (t, J =
6.4 Hz, 2 H, CH2OBn), 3.78 (dd, J = 10.8, 7.1 Hz, 1 H, CHCHaH-
bOTBS), 4.00 (dd, J = 10.8, 3.0 Hz, 1 H, CHCHaHbOTBS), 4.46–
4.50 (m, 1 H, CHOTBS), 4.52 (d, JAB = 12.0 Hz, 1 H, OCHaHbPh),
4.48 (d, JAB = 12.0 Hz, 1 H, OCHaHbPh), 4.60 (d, JAB = 11.5 Hz,
1 H, CHOCHaHbPh), 4.88 (d, JAB = 11.5 Hz, 1 H, CHOCH-
aHbPh), 7.25–7.33 (m, 10 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = –5.4, –5.4, –4.5, –4.4, 9.6, 18.1, 18.2, 23.9, 25.8, 25.9,
26.1, 35.5, 35.7, 53.5, 65.1, 66.7, 70.0, 73.0, 74.5, 81.3, 85.5, 85.5,
99.3, 127.4, 127.5, 127.5, 127.7, 128.2, 128.3, 138.4, 138.8,
CDCl3): δ = 1.20 (d, J = 7.3 Hz, 3 H, CH3), 1.67–1.74 (m, 1 H, 190.2 ppm. IR (film): ν
CH(OH)CHaHb), 1.80–1.89 (m, 1 H, CH(OH)CHaHb), 2.93 (br.s,
= 836, 1095, 1256, 1677, 2209 cm–1
.
˜
max
HRMS (TOF MS EI+) calcd. for C39H62O5NaSi2 689.4034; found
1 H, CHMe), 3.18 (s, 3 H, CH3N), 3.63–3.71 (m, 2 H, CH2OBn), 689.4040.
3.66 (s, 3 H, NOCH3), 3.87 (s, 1 H, OH), 4.05 (dtd, J = 9.0, 3.7,
(3R,5S,7S,8R)-3-(Benzyloxy)-7-[2-(benzyloxy)ethyl]-4,4,8-trimethyl-
1.6 Hz, 1 H, CHOH), 4.52 (s, 2 H, OCH2Ph), 7.26–7.34 (m, 5 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.1, 31.9, 34.0,
39.5, 61.5, 68.4, 70.4, 73.3, 127.6, 127.7, 128.4, 138.2, 177.8 ppm.
1,6-dioxaspiro[4.5]decan-9-one (13): The ynone 12 (21.7 mg,
32.5 µmol, 100 mol%) was dissolved in dry MeOH (0.5 mL), and
camphorsulfonic acid (1.4 mg, 6.0 µmol, 18 mol%) was added. The
reaction mixture was allowed to stir at room temp. for 2 h 30 min,
after which the solvent was evaporated. The residue was dissolved
IR (liq. CHCl ): ν
= 1637, 3480 cm–1. 1H HRMS (TOF MS
max
˜
3
EI+) calcd. for C15H23NO4Na 304.1525; found 304.1519.
(2R,3S)-5-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-N-methoxy- in dry benzene (1 mL) and the reaction mixture was stirred for
N,2-dimethylpentanamide (11): The alcohol 10 (0.697 g, 2.5 mmol,
100 mol%) was dissolved in dry CH2Cl2 (20 mL) and cooled to
0 °C. 2,6-Lutidine (1.16 mL, 10 mmol, 400 mol%) was added, and
the reaction mixture was allowed to stir for 22 min, after which
TBSOTf (1.72 mL, 7.5 mmol, 200 mol%) was added dropwise. Af-
ter 15 min the reaction was quenched with sat. K2CO3 (20 mL).
15 min, after which pTsOH (2.7 mg, 14 µmol, 44 mol%) was added.
Stirring was continued for another 18 h. The reaction was
quenched by addition of TEA (0.02 mL), followed by sat. NaHCO3
(1 mL). H2O (1 mL) and toluene (3 mL) were added, the phases
were separated, and the aqueous one was extracted three times with
toluene (3 mL). The combined organic phases were extracted once
4124
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 4119–4126

Study of a Key Reaction in the Planned Synthesis of Calyculin C
FULL PAPER
with brine (5 mL) and dried with MgSO4. The crude product was
purified by step gradient column chromatography (5%, 10%, 15%
and 20% EtOAc/hexane in 50 mL portions), affording 13 (12.3 mg,
86%) as a light yellow oil. Rf (50% EtOAc/Hex, UV/PMA) = 0.61.
[α]2D0 = –5.7 (c = 0.5; CHCl3). 1H NMR (400 MHz, CDCl3): δ =
0.94 (s, 3 H, CH3), 1.07 (d, J = 7.1 Hz, 3 H, CHCH3), 1.16 (s, 3
H, CH3), 1.64–1.72 (m, 1 H, CHaHbCH2OBn), 1.81–1.90 (m, 1 H,
[1]
[2]
For reviews of spiroketals see: a) F. Perron, K. F. Albizati,
Chem. Rev. 1989, 89, 1617–1661; b) M. F. Jacobs, W. Kitching,
Current Organic Chemistry 1998, 2, 395–436.
This is not always the case; e. g. pectenotoxin-1: T. Yasumoto,
M. Murata, Y. Oshima, M. Sano, G. K. Matsumoto, J. Clardy,
Tetrahedron 1985, 41, 1019–1025. and erythronolide A anhy-
dride: D. Schomburg, P. B. Hopkins, W. N. Lipscomb, E. J. Co-
rey, J. Org. Chem. 1980, 45, 1544–1546; endusamycin J. R. Os-
carson, J. Bordner, W. D. Celmer, W. P. Cullen, L. H. Huang,
H. Maeda, P. M. Moshier, S. Nishiyama, L. Presseau, R. Shi-
bakawa, J. Tone, J. Antibiot. 1989, 42, 37–48.
a) A. M. P. Koskinen, P. M. Pihko, Current Trends in Organic
Synthesis 1999, 291–298; b) P. M. Pihko, A. M. P. Koskinen,
Synlett 1999, 1966–1968; c) P. M. Pihko, A. M. P. Koskinen,
M. J. Nissinen, K. Rissanen, J. Org. Chem. 1999, 64, 652–654;
d) P. M. Pihko, A. M. P. Koskinen, J. Org. Chem. 1998, 63, 92–
98; e) A. M. P. Koskinen, P. M. Pihko, Tetrahedron Lett. 1994,
35, 7417–7420; f) A. M. P. Koskinen, J. Chen, Tetrahedron Lett.
1991, 32, 6977–6980; g) M. K. Lindvall, P. M. Pihko, A. M. P.
Koskinen, J. Biol. Chem. 1997, 272, 23312–23316; h) K. Karis-
almi, A. M. P. Koskinen, M. Nissinen, K. Rissanen, Tetrahe-
dron 2003, 59, 1421–1427; i) K. Karisalmi, A. M. P. Koskinen,
Synthesis 2004, 9, 1331–1342; j) V. Rauhala, M. Nevalainen,
A. M. P. Koskinen, Tetrahedron 2004, 60, 9199–9204.
CHaHbCH2OBn), 2.28–2.34 (m, 1 H, CHMe), 2.30 (d, JAB
=
14.9 Hz, 1 H, CH2OCHaHbPh), 2.56 (d, JAB = 14.9 Hz, 1 H,
CH2OCHaHbPh), 3.46–3.55 (m, 2 H, CH2OBn), 3.59 (dd, J = 8.7,
6.7 Hz, 1 H, CH(OBn)CHaHbO), 3.82 (dd, J = 8.7, 7.9 Hz, 1 H,
CH(OBn)CHaHbO), 4.10 (dd, J = 7.6, 6.7 Hz, 1 H, CHOBn), 4.22
[3]
(td, J = 9.8, 3.0 Hz, 1 H, CHCH2CH2OBn), 4.43 (dd, JAB
=
11.9 Hz, 1 H, CHOCHaHbPh), 4.44 (d, JAB = 11.8 Hz, 1 H,
CCHaHbC(O)CH), 4.47 (dd, JAB = 11.8 Hz, 2 H, CCHaHbC(O)
CH), 4.54 (d, JAB = 11.9 Hz, 1 H, CHOCHaHbPh), 7.28–7.37 (m,
10 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.5, 17.2,
20.3, 31.7, 40.9, 47.6, 48.4, 67.0, 67.2, 69.3, 73.0, 73.1, 84.6, 110.1,
127.4, 127.7, 127.7, 128.4, 128.4, 138.2, 138.4, 209.9 ppm. IR (film):
ν
˜
= 1102, 1719 cm–1. HRMS (TOF MS EI+) calcd. for
max
C27H34O5Na 461.2304; found 461.2306.
(3R,5S,7S,8R,9R)-3-(Benzyloxy)-7-[2-(benzyloxy)ethyl]-4,4,8-tri-
methyl-1,6-dioxaspiro[4.5]decan-9-ol (14): The spiroketal 13 (6 mg,
13.7 µmol, 100 mol%) was dissolved in dry THF (0.1 mL) and co-
oled to –78 °C. -Selectride (41 µL, 41 µmol, 300 mol%) was added
dropwise, and the reaction mixture was allowed to stir for 1 h
23 min before quenching by addition of MeOH (0.2 mL), NaOH
(2.0 , 0.1 mL), H2O2 (30%, 0.1 mL) and THF (2 mL). The reac-
tion mixture was allowed to stir for 37 min at 0 °C and 38 min at
room temp., after which H2O (1 mL) and Et2O (3 mL) were added.
The phases were separated and the aqueous one was extracted five
times with Et2O (3 mL). The combined organic phases were ex-
tracted once with brine (5 mL) and dried with MgSO4. The crude
product was purified by step gradient column chromatography
(10 %, 20 %, 30 %, 40 % and 50 % EtOAc/hexane in 20 mL por-
tions), affording 14 (4.1 mg, 68%) as a colourless oil. Rf (50 %
[4]
[5]
Y. Kato, N. Fusetani, V. Matsunaga, V. Hashimoto, V. Fujita,
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2002, 43, 1–2.
[6]
Previous synthetic approaches to calyculins: a) O. P. Anderson,
A. G. M. Barrett, J. J. Edmunds, S.-I. Hachiya, J. A. Hendrix,
K. Horita, J. W. Malecha, C. J. Parkinson, A. VanSickle, Can.
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A. G. M. Barrett, J. J. Edmunds, K. Horita, C. J. Parkinson, J.
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S. W. Gerritz, A. Sawabe, T. Noda, S. A. Filla, S. Masamune,
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Y. Hamada, T. Shioiri, Chem. Commun. 1996, 871–872; g) A. B.
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a) D. Seyferth, R. S. Marmor, P. Hilbert, J. Org. Chem. 1971,
36, 1379–1386; b) J. C. Gilbert, U. Weerisooriya, J. Org. Chem.
1982, 47, 1837–1845.
The absolute configuration is based on the accepted mnemonic
for the Sharpless AD. [H. C. Kolb, M. S. VanNieuwenzhe,
K. B. Sharpless, Chem. Rev. 1994, 94, 2483–2547.] This is fur-
ther corroborated by the conversion to the spiroketal and its
spectroscopic data.
EtOAc/Hex, UV/PMA) = 0.51. [α]2D0 = –9.8 (c = 0.31; CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 0.82 (d, J = 7.2 Hz, 3 H, CHCH3),
0.93 (s, 3 H, CH3), 1.06 (s, 3 H, CH3), 1.61–1.67 (m, 3 H, CHMe,
CHaHbCH2OBn, CCHaHbCH(OH)CH), 1.72–1.79 (m, 2 H,
CHaHbCH2OBn, CCHaHbCH(OH)CH), 3.45–3.54 (m, 2 H,
CH2OBn), 3.60 (dd, J = 8.6, 6.5 Hz, 1 H, CH(OBn)CHaHbO), 3.65
(d, J = 9.7 Hz, 1 H, OH), 3.79 (qd, J = 9.7, 3.1 Hz, 1 H, CHOH),
3.86 (dd, J = 8.6, 7.8 Hz, 1 H, CH(OBn)CHaHbO), 4.05 (dd, J =
7.7, 6.5 Hz, 1 H, CHOBn), 4.22 (td, J = 9.9, 2.9 Hz, 1 H,
CHCH2CH2OBn), 4.43 (d, JAB = 11.8 Hz, 1 H, OCHaHbPh), 4.46
(d, JAB = 12.0 Hz, 1 H, OCHaHbPh), 4.50 (d, JAB = 12.0 Hz, 1 H,
OCHaHbPh), 4.54 (d, JAB = 11.8 Hz, 1 H, OCHaHbPh), 7.28–7.38
(m, 10 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.6, 17.3,
20.4, 28.3, 29.7, 32.6, 37.9, 47.8, 63.4, 67.5, 69.5, 71.0, 73.0, 84.7,
[7]
[8]
109.5, 127.4, 127.6, 127.7, 128.4, 138.5, 138.5 ppm. IR (liq): ν
˜
max
= 1248, 3608 cm–1. HRMS (TOF MS EI+) calcd. for C27H36O5Na
463.2460; found 463.2469.
[9]
a) U. Widmer, Synthesis 1987, 6, 568–570; b) T. Iversen, D. R.
Bundle, J. Chem. Soc., Chem. Commun. 1981, 1240–1241; c)
H.-P. Wessel, T. Iversen, D. R. Bundle, J. Chem. Soc., Perkin
Trans. 1 1985, 2247–2251.
Acknowledgments
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a) S. Ohira, Synth. Commun. 1989, 19, 561–564; b) M. Kita-
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Durand, G. Reginato, A. Riu, Tetrahedron 2002, 58, 5159–
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Funding and financial support provided by the Finnish Academy,
the Ministry of Education, the Jenny and Antti Wihuri Foundation
and the Emil Aaltonen Foundation are gratefully acknowledged.
We would like to thank Dr. Jari Koivisto at Helsinki University of
Technology for assistance with NMR spectra.
Eur. J. Org. Chem. 2005, 4119–4126
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4125

V. Rauhala, K. Nättinen, K. Rissanen, A. M. P. Koskinen
FULL PAPER
son, Org. Lett. 2001, 3, 2945–2948; f) S. Müller, B. Liepold,
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refinement, 1997, University of Göttingen, Germany.
Received: March 18, 2005
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7159–7161.
Published Online: August 16, 2005
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4126
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 4119–4126