Synthesis of the spiroacetal fragment of broussonetine H

Article abstract of DOI:10.1016/S0040-4020(03)00949-9

(2S,6S)-2-(3-Bromopropyl)-1,7-dioxaspiro[5.5]undecane 3 was prepared by the addition of the acetylide derived from (4S)-4-benzyloxy-7-tert-butyldiphenylsilyloxyhep-1-yne 8 to δ-valerolactone 6 followed by treatment with hydrogen and palladium on charcoal which effected hydrogenation of the alkyne, hydrogenolysis of the benzyl ether and subsequent spiroacetal formation. The (4S)-stereochemistry in acetylene 8 was established by addition of trimethylsilylacetylene 10 to (2S)-epoxide 9, which in turn is derived from L-glutamic acid 11.

Full text of DOI:10.1016/S0040-4020(03)00949-9

Tetrahedron 59 (2003) 5861–5868
Synthesis of the spiroacetal fragment of broussonetine H
a
b
Margaret A. Brimble,a Jae H. Park and Carol M. Taylor
,
*
aDepartment of Chemistry, University of Auckland, Private Bag 92019, 23 Symonds St., Auckland, New Zealand
bInstitute of Fundamental Sciences, Massey University, Private Bag 11-222, Palmerston North, New Zealand
Received 24 April 2003; revised 19 May 2003; accepted 12 June 2003
Abstract—(2S,6S)-2-(3-Bromopropyl)-1,7-dioxaspiro[5.5]undecane 3 was prepared by the addition of the acetylide derived from (4S)-4-
benzyloxy-7-tert-butyldiphenylsilyloxyhep-1-yne 8 to d-valerolactone 6 followed by treatment with hydrogen and palladium on charcoal
which effected hydrogenation of the alkyne, hydrogenolysis of the benzyl ether and subsequent spiroacetal formation. The
(4S)-stereochemistry in acetylene 8 was established by addition of trimethylsilylacetylene 10 to (2S)-epoxide 9, which in turn is derived
from L-glutamic acid 11.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
sphingosine. One of the more exotic examples is brousso-
netine H (1)2c (Fig. 1(b)), which features a 1,6-dioxaspiro-
[5.5]undecane unit. Given the individual importance of both
spiroacetals5 and hydroxylated pyrrolidines6,7 we were
attracted to broussonetine H (1) as a synthetic target.8 We
report herein, an enantioselective synthesis of the spiro-
acetal domain.
The broussonetines and broussonetinines are a family of
alkaloids characterized by a hydroxylated pyrrolidine
moiety (Fig. 1(a)).1 To-date, Kusano and co-workers have
reported the isolation and structure determination of 30
congeners from the hot water extracts of the bark of
Broussonetia kazinoki SIEB (Moraceae),2 a deciduous tree
distributed throughout Asia. The cortex is a raw material for
handmade Japanese paper known as ‘washi’, and various
parts of the tree have been used in Chinese folk medicine.
The isolated compounds have demonstrated glycosidase
inhibition properties, which is hardly surprising given the
structural resemblance to 2,5-dideoxy-2,5-imino-D-manni-
2. Results and discussion
We embarked upon a synthetic strategy that would lead to
the rapid assembly of broussonetine H and be amenable to
the synthesis of natural and novel analogues. Thus, our
primary disconnection involved cleavage of the C6–C7
bond to yield a suitably protected prolinal derivative 2
(where P is an unspecified protecting group) and alkyl
bromide 3 (Scheme 1). In a forward sense, it was envisaged
that addition of the Grignard reagent derived from 3 to the
aldehyde in compound 2, would amalgamate the two
fragments. The stereochemistry at C6 would be generated
during this key step and we recognized that the inherent
stereochemistry in the two fragments will influence this.
tol
(2,5-dihydroxy-methyl-3,4-dihydroxypyrrolidine,
DMDP).3 Most of the broussonetines have 2R,3R,4R and
5R configurations around the periphery of the pyrrolidine
ring, although a subset have the 3S configuration. Diversity
arises in the nature of the thirteen carbon ‘side-chain’
attached at C5. Biosynthetic studies have led to the proposal
that C2, C3 and the CH2OH group at C2 are derived from D-
serine and the remaining carbons arise from palmitoyl-CoA4
via a pathway akin to that involved in the assembly of
Figure 1. (a) General structure; (b) broussonetine H (1).
Keywords: broussonetines; spiroacetal fragment; glutamic acid.
*
Corresponding author. Tel.: þ64-9-3737599; fax: þ64-9-3737422; e-mail: m.brimble@auckland.ac.nz
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00949-9

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M. A. Brimble et al. / Tetrahedron 59 (2003) 5861–5868
availability of starting materials (L-glutamic acid vs D-
glutamic acid, vide supra). Disconnection of the spiroacetal
functionality leads to acyclic precursor 5. It was anticipated
that the existing stereogenic centre in 5 would govern the
formation of the new stereogenic centre at C6, resulting in
the 2S,6S stereochemistry of the target molecule. Addition
of an anion derived from either sulfone 7 or acetylene 810 to
d-valerolactone was expected to assemble the carbon
skeleton.
The racemic sulfone (^)-7 was prepared and the anion
generated, as evidenced by successful incorporation of
deuterium, upon quenching with D2O. Unfortunately,
addition of the anion derived from (^)-7 to d-valerolactone,
and other electrophiles, was unsuccessful.11
Scheme 1. Retrosynthetic analysis of broussonetine H (1).
Our attention therefore quickly turned to the formation of
acetylene 8. Initial studies with racemic material11,12 were
encouraging and so 8 was prepared in optically active form
via epoxide 913 (Scheme 2). Epoxide 9 has been prepared on
a number of occasions and the route we adopted is detailed
in Scheme 3. Diazotization of L-glutamic acid 11 affords a
g-lactone carboxylic acid14 which can be reduced to triol
12.15 The availability of triol 12 in our laboratory
encouraged us to utilize this intermediate in the preparation
of epoxide 9. The 1,2-diol could be protected as an
acetonide to give compound 13.16 The primary alcohol
was protected as its tert-butyldiphenylsilyl ether (compound
14) then hydrolysis of the acetonide gave diol 15.16b–d The
diol was converted to epoxide 9 in a two-step procedure,
following the conditions reported by Yuasa et al.16b,c The
lithium acetylide generated from trimethylsilylacetylene 10
reacted with epoxide 9, under Yamaguchi conditions,17 to
While the absolute configuration at C6 in broussonetine H
has not been reported, the corresponding stereogenic centre
in broussonetines K and L,2e and in broussonetines R, S and
T,2h has been determined to be R, using a modification of the
Mosher method.
Further retrosynthetic analysis of the spiroacetal fragment is
illustrated in Scheme 2. The absolute configuration is not
known, but it is reasonable to assume that there will be a
favoured conformation in which there is a lone pair of
electrons antiperiplanar to each C–O bond, thereby gaining
maximum stability from the anomeric effect.9 The 2S,6S
configuration (depicted in Scheme 2) permits this, although
the natural configuration might equally well correspond to
the enantiomer (2R,6R). We have arbitrarily pursued a
synthesis of the 2S,6S isomer, based on the relative
Scheme 2. Retrosynthetic analysis of the spiroacetal fragment 3.

M. A. Brimble et al. / Tetrahedron 59 (2003) 5861–5868
5863
Scheme 3. Reagents, conditions and yields. (i) NaNO2, HCl, H2O, 08C, 54%; (ii) LiAlH4, THF, reflux, 47%; (iii) p-toluenesulfonic acid, acetone, 85%; (iv)
tBuPh2SiCl, imidazole, CH2Cl2, 87%; (v) PPTS, MeOH, 72%; (vi) TsCl, DMAP, NEt3, CH2Cl2, 95%; (vii) NaH, 18-crown-6, THF, 86%; (viii) HCCSiMe3,
nBuLi, BF3·OEt2, THF, 2788C; (ix) NaOMe, MeOH, 94%; (x) NaH, BnBr, nBu4NI, DMF, 88%.
give alcohol 16. The trimethylsilyl group in acetylene 16
was then removed to give 17, and the hydroxyl group
protected as a benzyl ether, to afford compound 8.
to the corresponding alkyl bromide 3 proved low yielding
(PPh3, CBr4, CH2Cl2, 10% yield),11 however, the two-step
procedure (Scheme 4) proved more efficient.
The elaboration of acetylide 8 to the spiroacetal target 3 is
illustrated in Scheme 4. The acetylide anion derived from
compound 8 was reacted with d-valerolactone (6) to afford a
mixture of keto-alcohol 18 and hemiacetal 19 in good yield.
This mixture was treated with hydrogen in the presence of
10% palladium on charcoal. This was expected to
simultaneously hydrogenate the triple bond and effect
hydrogenolysis of the benzyl ether to give compound 5. A
single product was obtained from the hydrogenation in 86%
yield, which, to our initial disappointment, was not
compound 5. Under the reaction conditions, compound 5
had spontaneously assembled into spiroacetal 20. It appears
that a trace of HCl present in the catalyst is sufficient to
promote the cyclization. We had anticipated that a second,
acid-catalyzed step would be required for this transform-
ation. The silyl ether protecting group was removed to
afford alcohol 4. Direct conversion of the primary alcohol 4
Comparison of the NMR data of compound 3 with that
reported by Shibano et al. for broussonetine H2c supports the
successful formation of the 1,6-dioxaspiro[5.5]undecane
ring system, as summarized in Table 1, where the
numbering system of the broussonetines has been adopted
for clarity.18
The Mosher ester derivative of compound 4 was prepared19
and 19F NMR analysis established that the enantiomeric
excess was only 70%. This forced us to look back over the
synthesis to ascertain where the stereochemical integrity
had been lost. Comparison of [a]D values with those
reported previously in the literature (see Section 4) for
compounds 9 and 13 suggested that their e.e.’s were in the
order of 80%, i.e. considerable racemization had taken place
during the conversion of L-Glu 11 to compound 13. Herdeis
has reported that the lactone acid (intermediate in the
Scheme 4. Reagents, conditions and yields. (i) nBuLi, BF3·OEt2, THF, 2788C, then d-valerolactone 6, 86%; (ii) H2, Pd/C, EtOAc, 86%; (iii) nBu4NF, THF,
96%; (iv) MsCl, DMAP, pyridine, 78%; (v) LiBr, acetone, reflux, 85%.

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M. A. Brimble et al. / Tetrahedron 59 (2003) 5861–5868
Table 1. 13C NMR chemical shifts
performed using Merck Kieselgel 60 (230–400 mesh) with
the indicated solvents. Thin layer chromatography (TLC)
was carried out on precoated silica plates (Merck Kieselgel
60F254) and compounds were visualized by UV fluorescence
or by staining with vanillin in methanolic sulfuric acid and
heating. Infrared spectra were recorded with a Perkin–
Elmer 1600 series Fourier-transform infrared spectrometer
as thin films between sodium chloride plates. Absorption
maxima are expressed in wavenumbers (cm21) with the
following abbreviations: s¼strong, m¼medium, w¼weak
1
and br¼broad. H and 13C NMR spectra were obtained
using a Bruker DRX-400 or a Bruker AM 200 spectrometer.
All chemical shifts are given in parts per million (ppm)
downfield from tetramethylsilane as internal standard (1H)
or relative to CDCl3 (13C) and J values are given in Hz. 1H
NMR data are tabulated as s, singlet; d, doublet; t, triplet; q,
quartet, m, multiplet, br, broad. High resolution mass
spectra were recorded using a VG7070 mass spectrometer
operating at nominal accelerating voltage of 70 eV.
Chemical ionisation (CI) mass spectra were obtained with
ammonia as the reagent gas. Optical rotations were
measured on a Perkin–Elmer 341 polarimeter. Samples
were prepared at the concentration indicated (measured in
g/100 cm3) in the solvent stated.
Carbon
Broussonetine H
(1) d (pyridine-d5) 125 MHz
Compound 3 d
(CDCl3) 100 MHz
C20
35.27
23.10
37.22
69.21
31.61
19.36
35.88
95.36
36.27
19.10
25.82
60.22
35.0
25.4
34.1
68.4
31.1
18.6
35.8
95.4
35.3
18.7
29.4
60.4
C30
C40
C50
C60
C70
C80
C90
4.1.1. (4S)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)propan-1-
ol (13). A solution of (2S)-pentane-1,2,5-triol 12 (6.02 g,
50.2 mmol) and p-toluenesulfonic acid (0.19 g, 2.01 mmol)
in acetone (60 mL) was stirred at room temperature under
nitrogen for 3 days. The reaction mixture was diluted with
ethyl acetate, washed with sat. aq. NaHCO3, dried over
MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash column chromatography,
eluting with 1:3 ethyl acetate–hexane to give (4S)-3-(2,2-
dimethyl-1,3-dioxolan-4-yl)propan-1-ol 13 (7.22 g, 90%) as
a pale yellow oil. [a]2D0¼þ12.2 (c¼1.03, CH2Cl2) lit.16a
[a]2D0¼þ15.3 (c¼2.45, CH2Cl2); lit.20 [a]2D2¼þ12.08
(c¼1.05, CH2Cl2); 1H and 13C NMR spectra were in
agreement with those reported in the literature.16a,21
C100
C1100
C12
C130
conversion of 11!12) is susceptible to racemization.14b
However, we suspect that epimerization at C-2 is taking
place during the formation of acetonide 13 from triol 12, as
proposed by Sugai et al.20 Indeed, Mori et al. have reported
poor optical purity of (þ)-ipsdienol prepared via the
analogous derivatization of 2R-butane-1,2,4-triol.21
Syntheses which converted L-glutamic acid 11 to acetonide
13, via a slightly different series of reactions,16a appear to
give compounds with established optical activity. We
therefore, concur with the opinion of others that triol 12 is
an epimerizable intermediate that should be avoided.
4.1.2. (4S)-tert-Butyl-[3-(2,2-dimethyl-1,3-dioxolan-4-
yl)propoxy]diphenylsilane (14). A solution of (4S)-3-
(2,2-dimethyl-1,3-dioxolan-4-yl)-propan-1-ol 13 (0.82 g,
5.0 mmol), tert-butyldiphenylsilyl chloride (1.43 mL,
5.5 mmol) and imidazole (0.68 g, 10.0 mmol) in CH2Cl2
(30 mL) was stirred at room temperature under nitrogen for
16 h. The reaction mixture was diluted with CH2Cl2
(50 mL), washed with brine (2£50 mL), dried over
MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash column chromatography,
eluting with 1:20 ethyl acetate–hexane to give (4S)-tert-
butyl-[3-(2,2-dimethyl-1,3-dioxolan-4-yl)propoxy]diphenyl-
silane 14 (1.73 g, 87%) as a pale yellow oil. [a]2D0¼þ6.9
(c¼1.02, CH2Cl2) lit.16d [a]D20¼28.6 (c¼1.07, CHCl3) for
the enantiomer. 1H and 13C NMR spectra were in agreement
with the data reported for the R-enantiomer.16d
3. Conclusion
(2S,6S)-2-(3-Bromopropyl)-1,7-dioxaspiro[5.5]undecane 3
has been prepared in enantioenriched form in eight steps
starting from (2S)-epoxide 9, trimethylsilylacetylene 10 and
d-valerolactone 6. Spiroacetal 3 is a potentially useful
intermediate for the construction of broussonetine H and
analogues thereof.
4. Experimental
4.1.3. (2S)-5-(tert-Butyldiphenylsilyloxy)pentane-1,2-diol
(15). A solution of (4S)-tert-butyl-[3-(2,2-dimethyl-1,3-
dioxolan-4-yl)propoxy]diphenylsilane 14 (0.51 g) and pyr-
idinium p-toluenesulfonate (51 mg, 10% w/w) in methanol
(20 mL) was stirred at room temperature under nitrogen for
5 h. The reaction mixture was concentrated under reduced
4.1. General details
All reactions were conducted in flame-dried or oven-dried
glassware under a dry nitrogen atmosphere unless otherwise
noted. Tetrahydrofuran was dried over sodium/benzophe-
none and distilled prior to use. Flash chromatography was

M. A. Brimble et al. / Tetrahedron 59 (2003) 5861–5868
t
5865
t
pressure. The residue was purified by flash column
chromatography, eluting with 1:3 ethyl acetate–hexane to
give (2S)-5-(tert-butyldiphenyl-silyloxy)pentane-1,2S-diol
15 (0.31 g, 72%) as a pale yellow oil. [a]2D0¼21.08
(c¼1.03, CH2Cl2) lit.16c [a]D20¼21.27 (c¼1.73, CH2Cl2)
and lit.16d [a]D19¼þ1.0 (c¼0.39, CHCl3) for the R-enantiomer.
1H and 13C NMR spectra were in agreement with those
reported in the literature.16c,d
19.1 (quat, Bu), 26.8 (CH3, Bu), 28.7 (CH2, C-6), 28.8
(CH2, C-3), 33.1 (CH2, C-5), 64.0 (CH2, OCH2), 69.8 (CH
CHOH), 87.3 (quat, C-1), 103.4 (quat, C-2), 127.6 (CH, Ph),
129.6 (CH, Ph), 133.6 (quat, Ph), 135.5 (CH, Ph); m/z (CI)
439 (MHþ, 100%), 381 (M2tBu, 7%), 361 (M2Ph, 5%),
199 (M2SiPht2Bu, 17%).
4.1.6. (4S)-7-(tert-Butyldiphenylsilyloxy)hept-1-yn-4-ol
(17). A solution of (4S)-7-(tert-butyldiphenylsilyloxy)-1-
trimethylsilylhept-1-yn-4-ol 16 (1.01 g, 2.31 mmol) and
sodium methoxide (0.25 g, 4.62 mmol) in methanol
(10 mL) was stirred at room temperature under nitrogen
for 5 h. The reaction mixture was concentrated under
reduced pressure, diluted with EtOAc (100 mL), washed
with brine (100 mL), dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was
purified by flash column chromatography, eluting with
10:1 hexane-ethyl acetate to give (4S)-7-(tert-butyldiphe-
nylsilyloxy)hept-1-yn-4-ol 17 (0.79 g, 94%) as a colour-
less oil; [a]2D0¼22.25 (c¼1.20, CHCl3); Rf: 0.44 (1:5
ethyl acetate–hexane). Found: C, 75.35; H, 8.42.
C23H30O2Si requires C, 75.36; H, 8.25%. Found (CI):
MHþ, 367.2098. C23H31O2Si, requires MH, 367.2093;
nmax (film)/cm21 3430 (O–H), 3301 (uC–H), 2110
(CuC), 1110 (Si–O–C), 703 (–CvCH); dH (400 MHz,
4.1.4. (2S)-5-tert-Butyldiphenylsilyloxy-1,2-epoxypen-
tane (9). p-Toluenesulfonyl chloride (0.13 g, 0.68 mmol),
4-(dimethylamino)pyridine (83 mg, 0.68 mmol) and triethy-
lamine (95 mL, 0.68 mmol) were added to a solution of
(2S)-5-(tert-butyldiphenylsilyloxy)pentane-1,2-diol
15
(0.22 g, 0.62 mmol) in CH2Cl2 (10 mL). The reaction
mixture was stirred at room temperature under nitrogen
for 16 h. The reaction mixture was diluted with CH2Cl2
(40 mL), washed with brine (2£30 mL), dried over MgSO4,
filtered and concentrated under reduced pressure. The crude
p-toluenesulfonate ester (0.21 g, 0.41 mmol), sodium
hydride (12 mg, 0.49 mmol) and 18-crown-6 (5 mg,
0.02 mmol) were dissolved in THF (5 mL). The reaction
mixture was stirred at room temperature under nitrogen for
16 h. The reaction mixture was diluted with EtOAc
(20 mL), washed with brine (2£10 mL), dried over
MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash column chromatography,
eluting with 1:10 ethyl acetate–hexane to give (2S)-5-tert-
butyldiphenylsilyloxy-1,2-epoxypentane 9 (0.12 g, 86%) as
a pale yellow oil. [a]2D0¼22.71 (c¼1.1, CHCl3) lit.16c
[a]2D0¼23.41 (c¼1.12, CHCl3), lit.22 [a]D¼21.6 (c¼1.35),
1H and 13C NMR spectra were in agreement with those
reported in the literature.16c
t
CDCl3) 1.05 (9H, s, Bu), 1.57–1.84 (4H, m, H-5, H-6),
2.04 (1H, t, J¼2.6 Hz, CuCH), 2.36–2.40 (2H, m, H-3),
2.56 (1H, d, J¼4.8 Hz, OH), 3.70 (2H, t, J¼5.6 Hz,
OCH2), 3.76–3.83 (1H, m, CHOH), 7.36–7.45 (6H, m,
Ph), 7.66–7.67 (4H, m, Ph); dC (100 MHz, CDCl3) 19.1
t
t
(quat, Bu), 26.8 (CH3, Bu), 27.3 (CH2, C-6), 28.7 (CH2,
C-3), 33.1 (CH2, C-5), 64.0 (CH2, OCH2), 69.7 (CH,
CvCH), 70.6 (CH, CHOH), 81.0 (quat, CuCH), 127.7
(CH, Ph), 129.6 (CH, Ph), 133.6 (quat, Ph), 135.6 (CH,
Ph); m/z (CI) 367 (MHþ, 28%), 309 (M2tBu, 21%), 289
(M2Ph, 11%), 199 (OSiHPh2, 100%).
4.1.5. (4S)-7-(tert-Butyldiphenylsilyloxy)-1-trimethylsi-
n
lylhept-1-yn-4-ol (16). Butyllithium (5.65 mL, 1.6 M in
hexane, 11.3 mmol) was added to a solution of trimethylsi-
lylacetylene 10 (1.60 mL, 11.3 mmol) in THF (30 mL) at
2788C under nitrogen. After 10 min, boron trifluoride
diethyl etherate (1.43 mL, 11.3 mmol) was added dropwise
to the reaction mixture. After 10 min, a solution of (4S)-1-
4.1.7. (4S)-4-Benzyloxy-7-tert-butyldiphenylsilyloxyhep-
1-yne (8). Benzyl bromide (0.38 mL, 3.29 mmol) and
tetrabutylammonium iodide (1.21 g, 1.63 mmol) were
added to a suspension of (4S)-7-(tert-butyldiphenylsilyl-
oxy)hept-1-yn-4-ol 17 (1.43 g, 3.27 mmol) and sodium
hydride (78 mg, 3.29 mmol) in DMF (40 mL). The reaction
mixture was stirred at room temperature under nitrogen for
16 h. Excess hydride was quenched with sat. aq. NH4Cl, the
reaction mixture washed with brine (2£40 mL), dried over
MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash column chromatography,
eluting with 98:2 hexane-ethyl acetate to give (4S)-4-
benzyloxy-7-tert-butyldiphenylsilyloxyhep-1-yne 8 (1.52 g,
88%) as a colourless oil; [a]2D0¼211.1 (c¼1.02, CHCl3); Rf:
0.43 (1:20 ethyl acetate–hexane). (Found: C, 78.63; H,
7.69. C30H36O2Si requires C, 78.90; H, 7.95%). Found (CI):
MHþ, 457.2563. C30H37O2Si, requires MH, 457.2556; nmax
(film)/cm21 3307 (uC–H), 2110 (CuC), 1111 (Si–O–C),
tert-butyldiphenylsilyloxy-4,5-epoxypentane
9
(1.28 g,
3.76 mmol) in THF (20 mL) was added dropwise. The
mixture was stirred at the same temperature for 20 min
n
following completion of the addition. Excess BuLi was
quenched with sat. aq. NH4Cl and the reaction mixture
diluted with EtOAc (100 mL), washed with brine (100 mL),
dried over MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by flash column
chromatography, eluting with 1:10 ethyl acetate–hexane
to give (4S)-7-(tert-butyldiphenylsilyloxy)-1-trimethylsilyl-
hept-1-yn-4-ol 16 (1.65 g, 92%) as a colourless oil; Rf: 0.63
(1:5 ethyl acetate–hexane); [a]2D0¼24.03 (c¼0.98, CHCl3).
Found: C, 71.38; H, 8.44. C26H38O2Si2 requires C, 71.17; H,
8.73%. (Found (CI): MHþ, 439.2485. C26H39O2Si2,
requires MH, 439.2489); nmax (film)/cm21 3430 (O–H),
3301 (uC–H), 2173 (CuC), 1111 (Si–O–C), 703 (–
CuCH); dH (400 MHz, CDCl3) 0.16 (9H, s, CH3Si), 1.05
t
702 (–CuCH); dH (400 MHz, CDCl3) 1.05 (9H, s, Bu),
1.58–1.86 (4H, m, H-5, H-6), 1.98 (1H, t, J¼2.7 Hz,
HCuC), 2.39 (1H, ddd, J¼2.7, 6.5, 16.9 Hz, H-3A), 2.46
(1H, ddd, J¼2.7, 5.1, 16.9 Hz, H-3B), 3.52–3.58 (1H, m,
CHO), 3.67 (2H, t, J¼6.1 Hz, CH2O), 4.53 (1H, d,
J¼11.7 Hz, CHAHBPh), 4.55 (1H, d, J¼11.7 Hz, CHAHB-
Ph), 7.21–7.42 (10H, m, Ph), 7.45–7.72 (5H, m, Ph); dC
t
(9H, s, Bu), 1.50–1.77 (4H, m, H-5, H-6), 2.37 (1H, dd,
J¼3.0, 11.5 Hz, H-3A), 2.45 (1H, dd, J¼3.0, 11.5 Hz, H-
3B), 2.51 (1H, br, OH), 3.69 (2H, t, J¼5.6 Hz, OCH2),
3.75–3.79 (1H, m, CHOH), 7.34–7.44 (6H, m, Ph), 7.64–
7.68 (4H, m, Ph); dC (100 MHz, CDCl3) 0.1 (CH3, CH3Si),
t
(100 MHz, CDCl3) 19.2 (quat, Bu), 23.8 (CH2, C-3), 26.9

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M. A. Brimble et al. / Tetrahedron 59 (2003) 5861–5868
t
(CH3, Bu), 28.2 (CH2, C-6), 30.1 (CH2 C-5), 63.7 (CH2,
CH2O), 69.9 (CH, CuCH), 71.2 (CH2, CH2Ph), 76.9 (CH,
CHO), 81.2 (quat, HCuC–C), 127.6 (CH, Ph), 127.7 (CH,
Ph), 128.3 (CH, Ph), 129.5 (CH, Ph), 133.9 (quat, Ph), 135.6
(CH, Ph), 138.4 (quat, Ph); m/z (CI) 457 (MHþ, 26%), 349
(M2PhCH2OH, 18%), 269 (CH2OSiPht2Bu, 11%), 91
(PhCH2, 100%).
(6H, m, Ph), 7.66–7.69 (4H, m, Ph); dC (100 MHz, CDCl3)
t
18.6 (CH2, C-4), 18.8 (CH2, C-10), 19.2 (quat, Bu), 25.4
0
t
(CH2, C-2 ), 26.9 (CH3, Bu), 29.0 (CH2, C-9), 31.2 (CH2,
C-10), 32.6 (CH2, C-3), 35.4 (CH2, C-11), 35.9 (CH2, C-5),
60.3 (CH2, C-8), 64.1 (CH2, OCH2), 68.9 (CH, C-2),
95.4 (quat, C-6), 127.6 (CH, Ph), 129.5 (CH, Ph),
134.1 (quat, Ph), 135.6 (CH, Ph); m/z (CI) 453 (MHþ,
97%), 395 (M2tBu, 100%), 375 (M2Ph, 12%), 199
(OSiHPh2, 49%).
4.1.8. (9S)-9-Benzyloxy-12-(tert-butyldiphenylsilyloxy)-
5-oxododec-6-yn-1-ol (18, 19). nButyllithium (50 mL,
1.6 M in hexane, 1.04 mmol) was added to a solution
of (4S)-4-benzyloxy-7-tert-butyldiphenylsilyloxyhep-1-yne
18 (0.49 g, 0.87 mmol) in THF (20 mL) at 2788C under
nitrogen. The reaction mixture was stirred at this tempera-
ture for 15 min then d-valerolactone 6 (96 mL, 1.04 mmol)
was added dropwise. The reaction mixture was stirred at this
4.1.10. (20S)-3-(1,7-Dioxaspiro[5.5]undec-2-yl)propan-1-
ol (4). Tetrabutylammonium fluoride (2.84 mL, 1 M in
THF, 2.84 mmol) was added to a solution of (2S)-2-[3-
(tert-butyldiphenylsilyloxy)prop-1-yl]-1,7-dioxaspiro[5.5]
undecane 21 (0.64 g, 1.42 mmol) in THF (30 mL). The
reaction mixture was stirred under nitrogen for 16 h.
Excess fluoride was quenched with sat. aq. NH4Cl and the
reaction mixture diluted with EtOAc (50 mL) then washed
with brine (2£50 mL). The organic layer was dried over
MgSO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography,
eluting with 3:1 hexane-ethyl acetate to give (4S)-3-(1,7-
dioxaspiro[5.5]undec-2-yl)propan-1-ol 4 (0.29 g, 96%) as
a colourless oil; [a]D20¼264.98 (c¼1.04, CHCl3); Rf: 0.23
(1:3 ethyl acetate–hexane). Found: C, 66.92; H, 10.47.
C12H22O3 requires C, 67.01; H, 10.35%. Found (EI): Mþ,
214.1564. C12H22O3, requires M, 214.1569; nmax (film)/
cm21 3369 (O–H), 977 (C–O–C); dH (400 MHz, CDCl3)
1.19–1.92 (16H, m, H-30, H-40, H-50, H-90, H-100, H-0 110,
H-2, H-3), 2.17 (1H, br, OH), 3.57–3.69 (5H, m, C-2 , C-
80, HOCH2); dC (100 MHz, CDCl3) 18.5 (CH2, C-40), 18.7
(CH2, C-100), 25.3 (CH2, C-2), 29.0 (CH2, C-90), 31.0
(CH2, C-3), 32.8 (CH2, C-30), 35.4 (CH2, C-50), 35.7
(CH2, C-110), 60.4 (CH2, C-80), 63.1 (CH2, CH2O), 69.1
(CH, C-20), 95.7 (quat, C-60); m/z (CI) 214 (Mþ, 4%), 196
(M2H2O, 6%), 101 (100%), 155 (M2(CH2)3OH, 15%),
141 (M2(CH2)4OH, 20%).
n
temperature for 1 h. Excess BuLi was quenched with sat.
aq. NH4Cl and the reaction mixture washed with brine
(2£10 mL). The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was
purified by flash column chromatography, eluting with 3:1
hexane-ethyl acetate to give (9S)-9-benzyloxy-12-(tert-
butyldiphenylsilyloxy)-5-oxododec-6-yn-1-ol 19 as an inse-
parable mixture with hemiacetal 20 (0.50 g, 86%) and as a
colourless oil; Rf: 0.27 (1:3 ethyl acetate–hexane). Found
(CI): MHþ, 557.3087. C35H44O4Si, requires MH, 557.3092;
n
max (film)/cm21 3412 (O–H), 2211 (CuC), 1671 (CvO),
1111 (Si–O–C); dH (400 MHz, CDCl3) (mixture of
compounds) 1.05 (9H, s), 1.29–1.35 (2H, m), 1.48–1.78
(7H, 2.41–2.63 (4H, m), 3.57–3.69 (3H, m, OCH2, OCH),
3.67 (2H, t, J¼6.0 Hz, OCH2), 4.53 (1H, d, J¼11.6 Hz,
CHAHBPh), 4.55 (1H, d, J¼11.6 Hz, CHAHBPh), 7.26–7.44
(10H, m, Ph), 7.60–7.71 (5H, m, Ph); dC (100 MHz, CDCl3)
(mixture of compounds) 13.8 (CH3), 19.2 (quat), 19.7
(CH2), 20.1 (CH2), 22.3 (CH2), 24.4 (CH2), 25.9 (CH2), 26.8
(CH3), 28.1 (CH3), 30.4 (CH2), 31.8 (CH2), 32.1 (CH2), 42.2
(CH2), 42.5 (CH2), 45.0 (CH2), 62.1 (CH2), 62.2 (CH2), 63.5
(CH2), 71.4 (CH2), 76.4 (CH), 82.0 (quat), 91.0 (quat),
127.6 (CH), 127.7 (CH), 128.4 (CH), 129.6 (CH), 133.8
(quat), 135.5 (CH), 138.0 (quat), 187.8 (quat); m/z (DCI)
557 (MHþ, 1%), 539 (M2H2O, 5%), 269 (CH2OSiPht2Bu,
11%), 141 (100%), 91 (PhCH2, 46%).
4.1.11. (20S)-3-(1,7-Dioxaspiro[5.5]undec-2-yl)prop-1-yl
methanesulfonate (21). Methanesulfonyl chloride (48 mL,
0.63 mmol) was added to a solution of 4-(dimethylamino)-
pyridine (18 mg, 0.16 mmol) in pyridine (5 mL). The
reaction mixture was stirred under nitrogen for 5 min. A
solution of (4S)-3-(1,7-dioxaspiro[5.5]undec-2-yl)propan-
1-ol 4 (67 mg, 0.31 mmol) in pyridine (5 mL) was added to
the mixture dropwise and the reaction stirred for 16 h. The
reaction mixture was diluted with CH2Cl2 (40 mL) and then
washed with 10% HCl (2£40 mL), sat. aq. NaHCO3
(40 mL) and brine (40 mL). The organic layer was dried
over MgSO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography,
eluting with 5:1 hexane-ethyl acetate to give (2S)-3-(1,7-
dioxaspiro[5.5]undec-2-yl)prop-1-yl methanesulfonate 22
(71 mg, 78%) as a colourless oil; [a]2D0¼241.4 (c¼1.00,
CHCl3); Rf: 0.32 (1:5 ethyl acetate–hexane). Found: C,
53.43; H, 8.13. C13H24O5S requires C, 53.40; H, 8.27%.
Found (EI): Mþ, 292.1341. C13H24O5S, requires M,
292.1345; nmax (film)/cm21 1354, 1175 (OvSvO), 983
(C–O–C); dH (400 MHz, CDCl3) 1.14–1.63 (12H, m, H-10,
H-040, H-90, H-100, H-2, H-3), 1.77–1.89 (3H, m, H-50B, H-
11 ), 1.99–2.10 (1H, m, H-50A), 3.01 (3H, s, SO2CH3), 3.59
(3H, m, CHO, H-80), 4.23–4.35 (2H, m, OCH2); dC
(100 MHz, CDCl3) 18.6 (CH2, C-40), 18.7 (CH2, C-100),
4.1.9. (2S)-2-[3-(tert-Butyldiphenylsilyloxy)prop-1-yl]-
1,7-dioxaspiro[5.5]undecane (20). 10% palladium on
charcoal (0.21 g) was added to a solution of (9S)-9-
benzyloxy-12-(tert-butyldiphenylsilyloxy)-5-oxo-dodec-6-
yn-1-ol 18,19 (0.43 g, 3.27 mmol) in ethyl acetate (20 mL).
The flask was evacuated then flushed with hydrogen and
stirred under a balloon of hydrogen for 2 h. The reaction
mixture was filtered and concentrated under reduced
pressure. The residue was purified by flash column
chromatography, eluting with 20:1 hexane-ethyl acetate to
give (2S)-2-[3-(tert-butyldiphenylsilyloxy)prop-1-yl]-1,7-
dioxaspiro[5.5]undecane 20 (0.37 g, 86%) as a colourless
oil; [a]2D0¼253.2 (c¼0.97, CHCl3); Rf: 0.27 (1:20 ethyl
acetate–hexane). Found: C, 74.50; H, 8.93. C28H40O3Si
requires C, 74.29; H, 8.91%. Found (CI): MHþ, 453.2825.
C28H41O3Si, requires MH, 453.2826; nmax (film)/cm21 1110
(Si–O–C), 1107 (C–O–C); dH (400 MHz, CDCl3) 1.05
(9H, s, tBu), 1.09–1.69 (13H, m, H-20, H-10, H-3, H-4, H-9,
H-10, H-11A), 1.76–1.87 (3H, m, H-5, H-11B), 3.51–3.62
(3H, m, H-2, H-8), 3.65–3.75 (2H, m, CH2OSi), 7.35–7.45

M. A. Brimble et al. / Tetrahedron 59 (2003) 5861–5868
5867
25.3 (CH2, C-2), 25.9 (CH2, C-90), 31.1 (CH2, C-3), 32.1
(CH2, C-30), 35.3 (CH2, C-110), 35.8 (CH2, C-50), 37.4 (CH3,
SO2CH3), 60.4 (CH2, 0C-80), 68.5 (CH, C-20), 70.4 (CH2, C-
1), 85.5 (quat, C-6 ); m/z (EI) 292 (Mþ, 5%), 196
(M2HOSO2CH3, 10%), 155 {M-(CH2)3OSO2CH3, 19%},
98 (CH3SO3H3, 100%).
CF3, S enantiomer); m/z (EI) 430 (Mþ, 19%), 189
(M2OC(O)CPh(CF3)(OMe), 89%), 101 (100%).
Acknowledgements
We thank Fares Fares for the preparation of triol 12 and JHP
thanks the Department of Chemistry at the University of
Auckland for a doctoral scholarship.
4.1.12. (2S)-(3-Bromopropyl)-1,7-dioxaspiro[5.5]unde-
cane (3). Lithium bromide (46 mg, 0.52 mmol) was added
to
a solution of (2S)-3-(1,7-dioxaspiro[5.5]undec-2-
yl)prop-1-yl methanesulfonate 22 (51 mg, 0.18 mmol) in
acetone (10 mL). The reaction mixture was heated under
reflux under nitrogen for 16 h then cooled to room
temperature, filtered and concentrated under reduced
pressure. The residue was purified by flash column
chromatography, eluting with 98:2 hexane-ethyl acetate
to give (2S)-(3-bromopropyl)-1,7-dioxaspiro[5.5]unde-
cane 3 (41 mg, 85%) as colourless oil; [a]2D0¼244.7
(c¼0.85, CHCl3); Rf: 0.47 (1:20 ethyl acetate–hexane).
Found: C, 52.04; H, 7.69. C12H21O2Br requires C, 51.99;
H, 7.64%. Found (EI): Mþ, 276.0722. C12H21O729Br,
requires M, 276.0725, Mþ, 278.0701. C12H21O821Br,
requires M, 278.0705; nmax (film)/cm21 1354, 1107 (C–
O–C), 510 (C–Br); dH (400 MHz, CDCl3) 1.14–1.69
(12H, m, H-3, H-4, H-9, H-10, H-10, H-20), 1.78–1.96
(3H, m, H-11, H-5B), 2.12–2.19 (1H, m, H-5A), 3.40–
3.53 (2H, m, H-8), 3.58–3.63 (3H, m, CHO, CH2Br); dC
(100 MHz, CDCl3) 18.6 (CH2, C-4), 18.7 (CH2, C-10),
25.4 (CH2, C-20), 29.4 (CH2, C-9), 31.1 (CH2, C-3), 34.1
(CH2, C-10), 35.0 (CH2, C-30), 35.3 (CH2, C-11), 35.8
(CH2, C-5), 60.4 (CH2, C-8), 68.4 (CH, C-2), 95.4 (quat,
C-6); m/z (EI) 276, 278 (Mþ, 5%), 197, (M2Br, 13%),
155, (M2(CH2)739 Br, 14%), 101 (100%).
References
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Broussonetines C and D: (b) Shibano, M.; Kitagawa, S.;
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nic acid (4S)-3-(1,7-dioxaspiro[5.5]undec-2-yl)propyl
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(10 mL, 0.06 mmol), (S)-a-methoxy-a-trifluoromethyl-
phenylacetyl chloride (25 mL, 0.09 mmol) and 4-
(dimethylamino)pyridine (23 mg, 0.2 mmol) and the
mixture stirred at room temperature under nitrogen for
16 h. The reaction mixture was diluted with CH2Cl2
(10 mL) and washed with brine (2£10 mL). The organic
layer was dried over MgSO4 and concentrated under
reduced pressure. The resultant residue was purified by
flash column chromatography, eluting with 5:1 hexane-
ethyl acetate to give (2S)-3,3,3-trifluoro-2-methoxy-2-
5. Jacobs, M. F.; Kitching, W. Curr. Org. Chem. 1998, 2,
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`
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a
[a]2D0¼7.01 (c¼0.51, CHCl3) dH (400 MHz, CDCl3)
1.09–1.97 (16H, m, H-2, H-3, H-30, H-40, H-50, H-90,
H-100, H-110), 3.54–3.58 (6H, m, CHO, OCH3, H-80),
4.37 (2H, t J¼8.8 Hz, H-1), 7.38–7.43 (3H, m, Ph),
7.51–7.54 (2H, m, Ph); dC (100 MHz, CDCl3) 18.6 (CH2,
C-40), 18.7 (CH2, C-100), 25.0 (CH2, C-2), 25.4 (CH2, C-
90), 31.1 (CH2, C-3), 32.4 (CH2, C-30), 35.4 (CH2, C-50),
35.8 (CH2, C-110), 55.4 (CH3, OCH3), 60.4 (CH2, C-80),
66.7 (CH2, CH2O), 68.5 (CH, CHO), 95.4 (quat, O–C–
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5868
M. A. Brimble et al. / Tetrahedron 59 (2003) 5861–5868
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