An expedient synthesis of spiroketals: Model studies for the calyculin C16-C25 fragment

Article abstract of DOI:10.1016/j.tet.2004.07.059

A new short strategy to prepare the spiroketal fragment of calyculins is presented. A novel Seyferth-Gilbert type homologation of hindered lactols to the corresponding alkynes has been achieved for the first time. The spirocyclization was achieved efficie

Full text of DOI:10.1016/j.tet.2004.07.059

Tetrahedron 60 (2004) 9199–9204
An expedient synthesis of spiroketals: model studies for the
calyculin C16–C25 fragment
*
Vesa Rauhala, Marta Nevalainen and Ari M. P. Koskinen
Department of Chemical Technology, Laboratory of Organic Chemistry, Helsinki University of Technology, Kemistintie 1, P.O. Box 6100,
Espoo FIN-02015 HUT, Finland
Received 28 April 2004; revised 30 June 2004; accepted 23 July 2004
Available online 27 August 2004
Abstract—A new short strategy to prepare the spiroketal fragment of calyculins is presented. A novel Seyferth–Gilbert type homologation of
hindered lactols to the corresponding alkynes has been achieved for the first time. The spirocyclization was achieved efficiently via a DIHMA
(double intramolecular hetero-Michael addition) process of this hindered ynone. The spirocyclization rate is not dependent on the
stereochemistry of the alkoxy substituent in the oxolane ring.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ynone 13a,b is highly sterically crowded, which might
affect the cyclization rate. Secondly, the formation of the
highly substituted alkyne 8 is not trivial. Thirdly, the
existence of the requisite alkoxy group in the oxolane ring
might affect the cyclization rate and/or the stability of the
ensuing spirocycle. To shed light on this latter question, we
decided to enter the spirocyclization with enantiopure 12
and racemic 8. Rate differences between the diastereomers
would thus become evident experimentally.
The 1,6-dioxaspiro[4.5]decane ring system is a common
motif, occurring in nearly 100 natural products.1 It is
noteworthy that in most of these structures, the configur-
ation of the stereogenic carbon atom is dictated by double
anomeric effect, placing the oxygen in the oxolane ring axial
with respect to the oxane ring (Fig. 1).2 Due to the wide
occurrence of such structures, a rapid and reliable entry into
the spirocyclic structure is highly desirable. This was of
special interest to us because of our ongoing efforts towards
the total synthesis of calyculin C, a potent protein
phosphatase inhibitor.3,4 In this paper we report our recent
results on a highly convergent strategy to achieve this goal.5
Our retrosynthetic strategy for the model spiroketal is based
on a convergent strategy (Scheme 1). The actual spiroketal
formation is based on the DIHMA (double intramolecular
hetero-Michael addition) process of a suitably derived
ynone.6 Thus, our penultimate goal became the ynone 13,
which would be available through a nucleophilic addition of
the alkyne 8 onto the Weinreb amide 12, in turn available
via Evans aldol methodology from propionyloxazolidinone
9 and benzyloxypropanal. The alkyne was envisioned to
arise through a Seyferth–Gilbert-type homologation7 of the
aldehyde (or lactol) corresponding to lactone 4.
Although seemingly well precedented, several questions
remained to be answered. First, the electrophilic end of the
Keywords: Enantioselectivity; Natural product; Spiroketals.
* Corresponding author. Tel.: C3589451-2526; fax: C3589451-2538;
e-mail: ari.koskinen@hut.fi
Figure 1. Spiroketal fragment of calyculin C.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.059

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V. Rauhala et al. / Tetrahedron 60 (2004) 9199–9204
lactone gave lactol 5 in near quantitative yield, ready for the
Seyferth–Gilbert type homologation to the alkyne without
further purification. If the initial ester aldol reaction was
allowed to warm to higher temperatures, the intermediate
alkoxide corresponding to 3 further reacted, by intramole-
cular benzoate transfer and ring closure, to give the hydroxy
lactone directly. Quenching the reaction mixture with
benzyl chloride gave 4 in a one-pot operation, however,
with yields typically below 25%. We therefore decided to
rely on the more reproducible two step operation.
Ohira’s reagent 6 is a mild alternative to the original
Seyferth–Gilbert homologation, widely used to transform an
aldehyde to the corresponding alkyne.8 In our case, the
lactol 5 was used as the aldehyde surrogate.9 The relative
sluggishness of the lactol for ring-chain tautomerism was
evident experimentally: Ohira’s reagent 6 had to be added
slowly (in five ca. 50 mol% portions over 5 days), and the
reaction temperature had to be kept low (between 36 and
44 8C) in order to achieve acceptable yields reproducibly
(60–79%, based on recovered starting material). Higher
reaction temperatures or faster addition of reagent 6 and the
base led to decomposed products. This successful procedure
represents the first successful example of using a hindered
lactol in the Seyferth–Gilbert homologation. Finally, the
secondary hydroxyl was protected (TBSOTf, lutidine, 88%)
to give the alkyne 8 ready for coupling.
The enantiopure fragment, Weinreb amide 12, was prepared
using the diastereoselective Evans syn-aldol reaction from
the known propionyloxazolidinone 9 and 3-benzyloxypro-
pionaldehyde (Scheme 3). Thus, reaction of the dibutyl-
boron Z-enolate of 9 and the aldehyde gave the desired 10 in
95% yield. Conversion of 10 to the Weinreb amide 11
(82%), followed by TBS protection under standard
conditions10 gave the coupling partner 12 (68%).
Scheme 1. Retrosynthetic analysis of spiroketal 1a.
2. Results
The alkyne 8 was prepared as shown in Scheme 2,
beginning with an addition of the ester enolate of ethyl
isobutyrate to 2-benzoyloxyacetaldehyde 2 affording the
hydroxy ester 3 in 63% yield. Protection of the hydroxy
group (NaH, BnCl, 75%) and DIBAL-H reduction of the
Fragments 8 and 12 were coupled using the Weinreb–Nahm
procedure to produce alkynone 13a,b.11 Spirocyclization
with the DIHMA procedure was then attempted using a
stepwise protocol.11 In the first step, the TBS protections
were cleavage by CSA in MeOH. Some spirocyclization
occurred already at this stage (TLC). Thus, the solvent was
removed and replaced with benzene, and addition of
p-TsOH took the spirocyclization to completion. Because
Scheme 2. Reagents: (i) LDA, Me2CHCO2Et, THF, K78 8C, then 2; (ii)
NaH, BnCl, DMF, THF, 0 8C; (iii) DIBAL-H, PhMe, K78 8C; (iv) 6,
K2CO3, MeOH, 36 8C; (v) TBSOTf, 2,6-lutidine, CH2Cl2, 0 8C.
Scheme 3. Reagents: (i) 9, Bu2BOTf, Et3N, CH2Cl2; then BnOCH2CH2-
CHO, K77 8C; (ii) MeOMeNH$HCl, AlMe3, THF, 0 8C; (iii) TBSCl, Im,
DMF, 0 8C.

V. Rauhala et al. / Tetrahedron 60 (2004) 9199–9204
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Scheme 4. Coupling of 8 and 12 and spirocyclization. Reagents: (i) BuLi, 8, then 12, THF K78 8C; (ii) CSA, MeOH, then p-TsOH, PhH, rt.
the alkyne 8 was not optically pure, the two diastereo-
isomers 1a and 1b were observed in a 1:1 diastereomeric
ratio (Scheme 4). This supports the conclusion that the
cyclization rate is not critically dependent on the existence
of a directing alkoxy group in the oxolane ring.
Elemental Analyzer 2400 CHN. HRMS spectra were
measured with Jeol JMS-DX 303 and Micromass LCT.
NMR spectra were measured with Bruker AMX 400 (1H
400.13 MHz, 13C 100.61 MHz).
4.1.1. 3-(Ethoxycarbonyl)-2-hydroxy-3-methylbutyl ben-
zoate 3. Diisopropylamine (2.82 mL, 20.1 mmol,
110 mol%) was dissolved in freshly distilled THF (20 mL)
at 0 8C. BuLi (2.3 M, 8.7 mL, 20.1 mmol, 110 mol%) was
added during 10 min and the light yellow solution was
cooled to K78 8C. Ethyl isobutyrate (2.69 mL, 20.1 mmol,
110 mol%) was added dropwise during 5 min. The light
yellow reaction mixture was stirred 1.5 h at K78 8C and
aldehyde 2 (3.0 g, 18.3 mmol, 100 mol%) in THF was
added dropwise over 20 min. After 2 h stirring at K78 8C,
the reaction was quenched with sat. NH4Cl (20 mL) and
allowed to warm up to rt. The aqueous phase was washed
three times with 30 mL of Et2O, the combined organic
phases were washed once with brine (20 mL) and dried with
Na2SO4. The product was purified by flash column
chromatography (30% EtOAc/hexane) affording 3 3.25 g
3. Conclusions
We have presented a new strategy to prepare the spiroketal
fragment of calyculins. A novel Seyferth–Gilbert type
homologation of hindered lactols to the corresponding
alkynes has been achieved for the first time. The
spirocyclization was achieved efficiently via a DIHMA
(double intramolecular hetero-Michael addition) process.
The spirocyclization rate is not dependent on the stereo-
chemistry of the alkoxy substituents in the oxolane ring.
Application of this protocol in the total synthesis of
calyculin C will be reported in due course.
(63%). Rf (50% EtOAc/hexane, UV/PMA)Z0.49; IR (nmax
,
4. Experimental
4.1. General
film) 1141, 1366, 1386, 1581, 1598, 1737, 3565 cmK1; H
NMR (400 MHz, CDCl3) d 1.25 (t, JZ7.1 Hz, 3H), 1.29 (s,
3H), 1.32 (s, 3H), 3.15 (d, JZ6.6 Hz, 1H), 4.05 (m, 1H),
4.14 (dd, JZ7.1, 4.9 Hz, 2H), 4.37 (dd, JZ7.3, 11.7 Hz,
1H), 4.48 (dd, JZ2.9, 11.7 Hz, 1H), 7.44 (m, 2H), 7.57 (m,
1H), 8.06 (m, 2H); 13C NMR (100 MHz, CDCl3) d 14.0,
20.9, 22.6, 45.4, 61.0, 66.2, 75.1, 128.4, 128.9, 129.7, 133.1,
166.7, 176.8; HRMS (TOF MS EIC) calcd for C15H21O5Na
303.1208, found 303.1221.
1
All reactions were conducted under a 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 pro analysis grade.
Melting points were determined on a Gallenkamp melting
point apparatus MFB-595 and are uncorrected. TLC was
conducted on Merck 0.25 mm silica gel 60 F plates and
samples were visualized with UV light, anisaldehyde, PMA
or ninhydrin staining. Flash chromatography was performed
using Merck silica gel 60 (230–400 mesh) as a stationary
phase. HPLC was performed with Waters 501 pump, Waters
486 tunable absorbance detector, Waters 746 data module
using the following columns: Shandon Hypersil Silica
Column with Waters Guard-Pake precolumn fitted with
Resolvee silica inserts for normal phase chromatography
and Daicel Chiralcel OD 25 cm!0.46 cm with Daicel
Chiracel OD 5 cm!0.46 cm precolumn for chiral chroma-
tography. Optical rotations were measured at 20 8C on a
Perkin–Elmer polarimeter 343. IR spectra were measured
with Perkin–Elmer Spectrum One.
4.1.2. 4-(Benzyloxy)-dihydro-3,3-dimethylfuran-2(3H)-
one 4. NaH (60% oil dispersion, 476 mg, 11.9 mmol,
110 mol%) in dry DMF was cooled to 0 8C. Ester 3 (3.03 g,
10.8 mmol, 100 mol%) in THF (6 mL) was added dropwise
at 0 8C. The reaction mixture was stirred for 5 min at 0 8C
and 15 min at rt. BnCl (1.37 mL, 11.9 mmol, 110 mol%)
was added dropwise and the reaction was stirred for 4 h at rt.
After quenching at 0 8C with sat. NH4Cl, the aqueous phase
was extracted three times with 25 mL of Et2O, the combined
organic phases were washed once with brine (50 mL) and
dried with MgSO4. After flash column chromatography
(15% EtOAc/hexane) lactone 4 was isolated (1.77 g, 75%).
Rf (30% EtOAc/hexane, UV/PMA)Z0.27; IR (nmax, film)
1
1773 cmK1; H NMR (400 MHz, CDCl3) d 1.26 (s, 3H),
1.28 (s, 3H), 3.91 (dd, JZ4.0, 5.1 Hz, 1H), 4.15 (dd, JZ4.0,
Elemental analyses were performed with Perkin–Elmer
10.1 Hz, 1H), 4.31 (dd, JZ5.1, 10.1 Hz, 1H), 4.59 (d, JABZ

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V. Rauhala et al. / Tetrahedron 60 (2004) 9199–9204
11.1 Hz, 2H), 7.30–7.39 (m, 5H); 13C NMR (100 MHz,
CDCl3) d 17.9, 23.3, 42.9, 68.9, 72.1, 81.8, 127.5, 128.0,
128.5, 137.4, 180.6; HRMS (EIC) calcd for C13H16O3
220.1099, found 220.1092.
phase dried with Na2SO4. Crude 8 was purified by column
chromatography (15% EtOAc/hexane) affording pure pro-
duct (0.161 g, 88%) as a slightly yellow oil. Rf (50% EtOAc/
hexane, UV/PMA)Z0.67; IR (nmax, film) 839, 1096, 1257,
1383, 2254, 3306, 3690 cmK1; 1H NMR (400 MHz, CDCl3)
d 0.07 (s, 3H), 0.08 (s, 3H), 0.92 (s, 9H), 1.20 (s, 3H), 1.27
(s, 3H), 2.13 (s, 1H), 3.36 (dd, JZ7.3, 2.7 Hz, 1H), 3.80 (dd,
JZ10.8, 7.3 Hz, 1H), 4.10 (dd, JZ10.8, 2.7 Hz, 1H), 4.78
(d, JABZ11.4 Hz, 2H), 7.24–7.38 (m, 5H); 13C NMR
(100 MHz, CDCl3) d K5.4, K5.3, 18.2, 24.4, 25.9, 27.1,
34.7, 65.4, 69.1, 74.5, 86.1, 90.0, 127.3, 127.8, 128.2, 139.0;
HRMS (TOF MS EIC) calcd for C20H32O2NaSi 355.2069,
found 355.2110.
4.1.3. 4-(Benzyloxy)-tetrahydro-3,3-dimethylfuran-2-ol
5. Lactone 4 (0.273 g, 1.24 mmol, 100 mol%) in toluene
(12 mL) was cooled to K78 8C. DIBAL-H (1 M in toluene,
2.11 mL, 2.11 mmol, 170 mol%) was added during 5 min.
After 14 min, the reaction was quenched by adding MeOH
(0.5 mL) and allowed to warm up to rt. The solution was
partitioned between 20 mL of 1 M HCl and 20 mL of
EtOAc, the phases were separated and the aqueous phase
was extracted three times with 15 mL of EtOAc. The
combined organic phases were washed once with 10 mL of
brine, dried with MgSO4 and evaporated affording crude 5
0.267 g, which was used without purification in the next
reaction. Rf (50% EtOAc/hexane, UV/PMA)Z0.36; 1H
NMR (400 MHz, CDCl3) d 1.01 (s, 3H), 1.24 (s, 3H), 3.58
(d, JZ12.1 Hz, 1H), 3.61 (d, JZ3.7 Hz, 1H), 4.05 (dd, JZ
4.1.6. (S)-4-Benzyl-3-((2S,3R)-5-benzyloxy-3-hydroxy-2-
methylpentanoyl)-2-oxazolidinone 10. (S)-4-Benzyl-3-
propionyl-2-oxazolidinone 9 was dissolved in 100 mL of
dry CH2Cl2 and cooled to 0 8C before dibutylboron triflate
(1 M in CH2Cl2, 41.2 mL, 41.2 mmol, 120 mol%) was
added dropwise keeping the internal temperature below
2 8C. The color changed to dark red-brown but when Et3N
(6.23 mL, 44.7 mmol, 130 mol%) was added (T % 2 8C) it
turned to yellow. After 40 min, the reaction mixture was
cooled to K77 8C and 3-benzyloxy-propionaldehyde (6.2 g,
37.8 mmol, 110 mol%) dissolved in 10 mL CH2Cl2 was
added slowly (45 min) keeping the internal temperature
stable. Stirring was continued for a further 3 h at K77 8C
and then for 30 min at 0 8C. Phosphate buffer (80 mL, pH
7.0) and methanol (60 mL) were added, and the mixture was
cooled to K10 8C before slow (15 min) addition of 120 mL
of (1:1) H2O2 (30%) and MeOH. The mixture was then
stirred for 30 min at 0 8C before organic solvents were
evaporated, Et2O was added and reaction was cooled to
0 8C. Sat. Na2S2O3 (120 mL) was added slowly (30 min)
and the phases were separated. The aqueous phase was
extracted three times with 80 mL Et2O and the combined
organic phases were washed once with 80 mL of sat.
NaHCO3 and 50 mL of brine and dried with Na2SO4. The
crude product was purified by flash column chromatography
(25% EtOAc/Hex) affording pure 10 (9.7 g, 71%). Rf (50%
EtOAc/Hex, UV/PMA)Z0.31; [a]2D0ZC44.7 (c 1.0;
10.5, 3.8 Hz, 1H), 4.23 (d, JZ10.2 Hz, 1H), 4.54 (d, JAB
Z
11.8 Hz, 2H), 4.81 (d, JZ11.9 Hz, 1H), 7.29–7.38 (m, 5H);
13C NMR (100 MHz, CDCl3) d 17.2, 24.0, 46.6, 70.9, 72.0,
85.3, 105.3, 127.6, 127.9, 128.5, 137.4; HRMS (TOF MS
EIC) calcd for C13H18O3Na 245.1154, found 245.1180.
4.1.4. 2-Benzyloxy-3,3-dimethylpent-4-yn-1-ol 7. Lactol 5
(0.214 g, 0.963 mmol, 100 mol%) was diluted in 10 mL of
dry MeOH and dimethyl 1-diazo-2-oxopropyl phosphonate
6 (0.370 g, 1.925 mmol, 200 mol%) and K2CO3 (0.266 g,
1.925 mmol, 200 mol%) were added. The reaction was
warmed to 36 8C and allowed to stir for 5 days, during
which more phosphonate 6 (0.092 g, 0.481 mmol, 50 mol%)
and K2CO3 (0.067 g, 0.481 mmol, 50 mol%) in 0.5 mL of
dry MeOH were added five times once a day. The blue–
green reaction mixture was evaporated to dryness and
dissolved in 30 mL of 1:1 mixture of Et2O and H2O. The
phases were separated and the aqueous one was extracted
four times with 10 mL of Et2O and dried with MgSO4.
Crude 7 was purified by column chromatography (15%
EtOAc/hexane) affording 0.122 g (58%) of a slightly yellow
oil. Rf (50% EtOAc/Hex, UV/anisaldehyde)Z0.50; IR
1
CHCl3); IR (nmax, film) 1111, 1694, 1780, 3480 cmK1; H
1
(nmax, film) 1096, 1382, 2254, 3306, 3690 cmK1; H NMR
NMR (400 MHz, CDCl3) d 1.28 (d, JZ7.0 Hz, 3H), 1.74
(m, 1H), 1.89 (m, 1H), 2.78 (dd, JZ13.2, 9.5 Hz, 1H), 3.26
(dd, JZ13.5, 3.3 Hz, 1H), 3.29 (d, JZ2.6 Hz, 1H), 3.69 (m,
2H), 3.82 (dq, JZ7.0, 3.7 Hz, 1H), 4.18 (m, 1H), 4.19 (m,
2H), 4.52 (s, 2H), 4.68 (m, 1H), 7.34–7.19 (m, 10H); 13C
NMR (100 MHz, CDCl3) d 11.1, 33.7, 37.8, 42.6, 55.2,
66.1, 68.4, 70.4, 73.3, 127.4, 127.7, 128.4, 129.0, 129.4,
135.1, 138.0, 153.1, 176.7; HRMS (EIC) calcd for
C23H27NO5 397.1889, found 397.1880.
(400 MHz, CDCl3) d 1.27 (s, 3H), 1.30 (s, 3H), 1.86 (dd, JZ
7.3, 5.3 Hz, 1H), 2.19 (s, 1H), 3.40 (dd, JZ6.6, 3.8 Hz, 1H),
3.77 (ddd, JZ11.9, 6.6, 5.3 Hz, 1H), 3.92 (ddd, JZ11.7,
7.5, 3.9 Hz, 1H), 4.75 (d, JABZ11.9 Hz, 2H), 7.29–7.38 (m,
5H); 13C NMR (100 MHz, CDCl3) d 24.7, 26.7, 34.7, 62.6,
69.8, 74.7, 85.6, 89.7, 127.8, 127.9, 128.5, 138.3; HRMS
(TOF MS EIC) calcd for C14H18O2NaSi 241.1204, found
241.1216.
4.1.5. (2-(Benzyloxy)-3,3-dimethylpent-4-ynyloxy)-tert-
butyldimethylsilane 8. The alcohol
4.1.7. (2S,3R)-5-(Benzyloxy)-3-hydroxy-N-methoxy-N,2-
dimethylpentanamide 11. A 25 mL 2-neck flask was
charged with N,O-Dimethyl hydroxylamine hydrochloride
(1.08 g, 11.1 mmol, 220 mol%) and 4 mL THF. The
suspension was cooled to K10 8C in a NaCl/ice-bath and
AlMe3 (5.3 mL, 10.6 mmol, 210 mol%) 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 rt before it
was cooled again to K10 8C. Oxazolidinone 10 (2.0 g,
5.0 mmol, 100 mol%) dissolved in a mixture (4:5) of
CH2Cl2 (2.9 mL) and THF (3.5 mL) was slowly added.
7
(0.120 g,
0.550 mmol, 100 mol%) was dissolved in dry CH2Cl2
(6 mL) and cooled to 0 8C. 2,6-Lutidine (0.256 mL,
2.2 mmol, 400 mol%) was added and the reaction mixture
was allowed to stir for 36 min before TBSOTf (0.253 mL,
1.1 mmol, 200 mol%) was added. After 12 min the reaction
was quenched with 3 mL of sat. K2CO3. The mixture was
partitioned between water (10 mL) and Et2O (10 mL) and
the phases were separated. The aqueous phase was extracted
three times with 10 mL of Et2O and the combined organic

V. Rauhala et al. / Tetrahedron 60 (2004) 9199–9204
9203
The mixture was stirred for 1 h at 0 8C and then poured into
a pre-cooled 0 8C mixture of aqueous HCl [0.5 M] (16 mL)
and CH2Cl2 (16 mL). This was stirred for 1 h 15 min at 0 8C
and the phases were separated. The aqueous phase was
extracted three times with 60 mL of CH2Cl2 and the
combined organic phases were washed once with 50 mL
of brine and dried with MgSO4. The crude product was
purified by step gradient column chromatography (1:3, 2:5,
1:1 and 3:5 EtOAc / hexane in 900 mL fractions) affording
11 as a light yellow oil (1.16 g, 82%). Rf (50% EtOAc/Hex,
d 0.01 (s, 3H), 0.04 (s, 3H), 0.06 (s, 3H), 0.07 (s, 3H), 0.84
(s, 9H), 0.91 (s, 9H), 1.13 (d, JZ6.9 Hz, 3H), 1.23 (s, 3H),
1.28 (s, 3H), 1.76–1.92 (m, JZ14.0, 6.4 Hz, 2H), 2.53–2.60
(m, JZ13.9, 6.9 Hz, 1H), 3.38 (dd, JZ7.1, 3.0 Hz, 1H),
3.49 (t, JZ6.5 Hz, 2H), 3.78 (dd, JZ10.8, 7.1 Hz, 1H), 4.00
(dd, JZ10.8, 3.0 Hz, 1H), 4.75 (d, JABZ11.5 Hz, 2H),
7.25–7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d K5.4,
K5.4, K4.5, K4.4, 9.5, 9.6, 18.1, 18.2, 23.9, 24.0, 25.8,
25.9, 26.1, 35.4, 35.7, 53.5, 65.1, 65.1, 66.7, 70.0, 73.0,
74.5, 81.3, 85.5, 85.5, 99.3, 127.4, 127.4, 127.5, 127.7,
127.7, 128.2, 128.3, 138.4, 138.7, 138.8, 190.2; HRMS
(TOF MS EIC) calcd for C39H62O5NaSi2 689.4034, found
689.4025.
UV/PMA)Z0.12; [a]2D0ZC11.4 (c 1.0; CHCl3); IR (nmax
,
film) 1102, 1637, 3468 cmK1; 1H NMR (400 MHz, CDCl3)
d 1.20 (d, JZ7.3 Hz, 3H), 1.89–1.66 (m, 2H), 2.93 (br s,
1H), 3.18 (s, 3H), 3.63–3.73 (m, 2H), 3.66 (s, 3H), 3.92 (s,
1H), 4.05 (m, 1H), 4.52 (s, 2H), 7.26–7.34 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 11.1, 31.9, 34.0, 39.5, 61.5,
68.3, 70.3, 73.2, 127.6, 127.6, 128.4, 138.2, 177.8; HRMS
(TOF MS EIC) calcd for C15H23NO4Na 304.1525, found
304.1550.
4.1.10. (7R,8S)-3-Benzyloxy-7-(2-benzyloxy-ethyl)-4,4,8-
trimethyl-1,6-dioxa-spiro[4.5]decan-9-one 1a and 1b.
The mixture of ynones 13a,b (13 mg, 19.5 mmol,
100 mol%) was dissolved in 0.5 mL of dry MeOH, and
camphor sulphonic acid (0.7 mg, 3.0 mmol, 15 mol%) was
added. The reaction was allowed to stir at rt for 2 h 20 min
before the solvent was evaporated. The residue was
dissolved in 1 mL benzene and the reaction was stirred for
3 h 30 min, after which time p-TsOH (1.4 mg, 7.4 mmol,
38 mol%) was added. Stirring was continued for another
15 h, and the reaction was quenched by adding TEA
(0.02 mL) followed by 1 mL of sat. NaHCO3. The phases
were separated and the aqueous one was extracted three
times with 3 mL of toluene. The combined organic phases
were extracted once with 5 mL of brine and dried with
MgSO4. The crude product was first purified by step
gradient column chromatography (5, 10, 15 and 20%
EtOAc/hexane in 50 mL portions) affording the two
diastereomers 1a and 1b (8.2 mg, 96%). The diastereomers
were separated with HPLC chromatography, which afforded
(4.1 mg each).
4.1.8. (2S,3R)-5-(Benzyloxy)-3-(tert-butyldimethylsilyl-
oxy)-N-methoxy-N,2-dimethylpentanamide 12. Alcohol
11 (0.50 g, 1.78 mmol, 100 mol%) and imidazole (0.61 g,
8.89 mmol, 500 mol%) were dissolved in 5 mL of dry DMF
and cooled to 0 8C. TBSCl (0.54 g, 3.55 mmol, 200 mol%)
in 5 mL DMF was added dropwise over 10 min to the
reaction after which the reaction was allowed warm up to rt.
After stirring for 43 h, the reaction was quenched with
20 mL of EtOAc and 20 mL of brine and stirred for 30 min.
The phases were separated and the aqueous phase was
washed three times with 20 mL of Et2O. The combined
organic phases were dried over MgSO4. The crude product
was purified by column chromatography (5% MTBE/Hex)
affording the product 12 (0.48 g, 68%). Rf (50% EtOAc/
Hex, UV/PMA)Z0.46; [a]2D0ZK2.4 (c 1.0; CHCl3); IR
1
(nmax, film) 836, 1103, 1663 cmK1; H NMR (400 MHz,
CDCl3) d 0.04 (s, 3H), 0.06 (s, 3H), 0.89 (s, 9H), 1.13 (d, JZ
7.0 Hz, 3H), 1.82–1.88 (m, 2H), 2.99 (br s, 1H), 3.13 (s,
3H), 3.49–3.56 (m, 2H), 3.59 (s, 3H), 4.03 (td, JZ8.0,
5.1 Hz, 1H), 4.47 (d, JABZ12.1 Hz, 2H), 7.24–7.33 (m,
5H); 13C NMR (100 MHz, CDCl3) d K4.5, K4.4, 14.5,
18.1, 25.9, 32.1, 35.4, 41.2, 61.2, 66.5, 71.3, 72.9, 127.4,
127.7, 128.3, 138.6, 176.3; HRMS (EIC) calcd for
C21H37NO4Si 395.2492, found 395.2512.
(Fraction 1) Rf (50% EtOAc/Hex, UV/PMA)Z0.59; Rt
(Shandon Hypersil 5m column, EtOAc/hexane, 1:20, flow
rate 1.0 mL/min, lZ254 nm)Z30.52 min; [a]2D0ZC105 (c
0.1; CHCl3); IR (nmax, film) 1718 cmK1 1H NMR
;
(400 MHz, CDCl3) d 0.94 (s, 3H), 1.07 (d, JZ7.0 Hz,
3H), 1.60 (s, 3H), 1.64–1.72 (m, 1H), 1.81–1.90 (m, 1H),
2.33 (qd, JZ7.0, 2.6 Hz, 1H), 2.45 (dd, JABZ14.8 Hz, 2H),
3.46–3.54 (m, 2H), 3.59 (dd, JZ8.8, 6.7 Hz, 1H), 3.59 (dd,
JZ8.7, 7.8 Hz, 1H), 4.12 (dd, JZ7.7, 6.7 Hz, 1H), 4.24 (td,
JZ9.8, 3.0 Hz, 1H), 4.47 (dd, JABZ11.9 Hz, 2H), 4.49 (dd,
JABZ11.8 Hz, 2H), 7.28–7.35 (m, 10H); 13C NMR
(100 MHz, CDCl3) d 10.5, 17.2, 20.3, 29.7, 40.8, 47.6,
66.9, 67.2, 69.3, 72.9, 73.1, 84.5, 110.0, 127.4, 127.7, 127.7,
128.4, 128.4, 138.2, 138.4, 209.9; HRMS (TOF MS EIC)
calcd for C27H34O5Na 461.2304, found 461.2318.
4.1.9. (3R,4S,9R/S)-1,9-Bis(benzyloxy)-3,10-di(tert-butyl-
silyloxy)-4,8,8-trimethyldec-6-yn-5-one 13a,b. The
alkyne 8 (0.057 g, 0.172 mmol, 200 mol%) was dissolved
in 1.7 mL of dry THF and cooled to K78 8C. BuLi (2.27 M,
83 ml, 0.189 mmol, 220 mol%) was added and the reaction
was allowed to stir for 1 h before the Weinreb amide 12
(0.034 g, 0.086 mmol, 100 mol%) in 0.9 mL of dry THF
was added. After 50 min, the reaction mixture was allowed
to warm up to rt and after another 2 h 15 min it was
quenched with 5 mL of H2O. Et2O (10 mL), H2O (5 mL)
and brine (5 mL) were added and the phases were separated.
The aqueous phase was extracted three times with 10 mL of
Et2O and the combined organic phases were dried with
MgSO4. The crude product was purified by step gradient
chromatography (150 mL 5% EtOAc/hexane, 150 mL 10%
EtOAc/hexane) affording 13a,b (0.045 g, 79%). Rf (50%
EtOAc/Hex, UV/PMA)Z0.66; IR (nmax, film) 838, 1095,
1257, 1669, 2208, 2247 cmK1; 1H NMR (400 MHz, CDCl3)
(Fraction 2) Rf (50% EtOAc/Hex, UV/PMA)Z0.59; Rt
(Shandon Hypersil 5m column, EtOAc/hexane, 1:20, flow
rate 1.0 mL/min, lZ254 nm)Z35.69 min; [a]2D0ZC90 (c
0.1; CHCl3); IR (nmax, film) 1718 cmK1 1H NMR
;
(400 MHz, CDCl3) d 0.91 (s, 3H), 1.11 (d, JZ7.1 Hz,
3H), 1.25 (s, 3H), 1.59–1.67 (m, 1H), 1.85–1.94 (m, 1H),
2.34 (qd, JZ7.2, 2.0 Hz, 1H), 2.42 (dd, JABZ14.5 Hz, 2H),
3.54–3.67 (m, 2H), 3.61 (dd, JZ6.4, 3.1 Hz, 1H), 3.67 (dd,
JZ9.7, 3.2 Hz, 1H), 4.16 (dd, JZ9.7, 6.4 Hz, 1H), 4.28 (td,
JZ10.6, 2.5 Hz, 1H), 4.30 (dd, JABZ12.1 Hz, 2H), 4.49
(dd, JABZ12.1 Hz, 2H), 7.23–7.36 (m, 10H); 13C NMR

9204
V. Rauhala et al. / Tetrahedron 60 (2004) 9199–9204
5. For previous synthetic approaches, see: (a) Anderson, O. P.;
Barrett, A. G. M.; Edmunds, J. J.; Hachiya, S.-I.; Hendrix,
J. A.; Horita, K.; Malecha, J. W.; Parkinson, C. J.; VanSickle,
A. Can. J. Chem. 2001, 79, 1562–1592. (b) Evans, D. A.;
Gage, J. R. Tetrahedron Lett. 1990, 31, 6129–6132. (c) Evans,
D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114,
9434–9453. (d) Barrett, A. G. M.; Edmunds, J. J.; Horita, K.;
Parkinson, C. J. J. Chem. Soc., Chem. Commun. 1992,
1236–1238. (e) Tanimoto, N.; Gerritz, S. W.; Sawabe, A.;
Noda, T.; Filla, S. A.; Masamune, S. Angew. Chem. 1994, 106,
674–677. See also Angew. Chem., Int. Ed. Engl., 1994, 33,
673–675. (f) Yokokawa, F.; Hamada, Y.; Shioiri, T. Chem.
Commun. 1996, 871–872. (g) Smith, A. B.; Friestad, G. K.;
Barbosa, J.; Bertounesque, E.; Hull, K. G.; Iwashima, M.; Qiu,
Y.; Salvatore, B. A.; Spoors, P. G.; Duan, J. J.-W. J. Am.
Chem. Soc. 1999, 121, 10468–10477. (h) Smith, A. B.;
Iwashima, M. Tetrahedron Lett. 1994, 35, 6051–6052.
(i) Smith, A. B.; Duan, J. J. W.; Hull, K. G.; Salvatore, B. A.
Tetrahedron Lett. 1991, 32, 4855–4858. (j) Scarlato, G. R.;
DeMattei, J. A.; Chong, L. S.; Ogawa, A. K.; Lin, M. R.;
Armstrong, R. W. J. Org. Chem. 1996, 61, 6139–6152. (k) Trost,
B. M.; Flygare, J. A. Tetrahedron Lett. 1994, 35, 4059–4062.
6. (a) Aiguade, J.; Hao, J.; Forsyth, C. J. Org. Lett. 2001, 3,
979–982. (b) Forsyth, C. J.; Hao, J.; Aiguade, J. Angew.
Chem., Int. Ed. 2001, 40, 3663–3667. (c) Forsyth, C. J.
Tetrahedron Lett. 2002, 43, 1–2.
(100 MHz, CDCl3) d 10.7, 16.6, 24.5, 29.7, 41.1, 49.0, 66.6,
67.0, 71.3, 72.5, 72.8, 85.4, 108.8, 127.1, 127.4, 127.5,
127.5, 128.3, 128.3, 128.4, 138.6, 138.6, 210.4; HRMS
(TOF MS EIC) calcd for C27H34O5Na 461.2304, found
461.2317.
Acknowledgements
Funding and financial support provided by the Finnish
Academy, the Ministry of Education, Jenny and Antti
Wihuri Foundation and Emil Aaltonen Foundation are
gratefully acknowledged. We would like to thank Mr. Y.
Masuda for the valuable work with the lactone fragment and
¨
Paivi Joensuu at the University of Oulu for providing the
high resolution mass spectroscopy data.
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