Enantiospecific synthesis of (+)-hyacinthacine A2

Article abstract of DOI:10.1002/ejoc.200500914

We report an efficient synthesis of (+)-hyacinthacine A₂ in six steps from (S)-N-Cbz-vinylgylcine. The key strategies were the olefin cross metathesis (CM), Sharpless asymmetric dihydroxylation, and a sequential double reductive cyclization. Wi

Full text of DOI:10.1002/ejoc.200500914

FULL PAPER
DOI: 10.1002/ejoc.200500914
Enantiospecific Synthesis of (+)-Hyacinthacine A2
Purnama Dewi-Wülfing[a] and Siegfried Blechert*[a]
Keywords: Olefin cross metathesis / Dihydroxylation / Hydrogenation / Alkaloids / Natural products
We report an efficient synthesis of (+)-hyacinthacine A2 in six
steps from (S)-N-Cbz-vinylgylcine. The key strategies were
the olefin cross metathesis (CM), Sharpless asymmetric dihy-
droxylation, and a sequential double reductive cyclization.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
The first synthesis of hyacinthacine A2, utilising ring-
closing metathesis as the key step, was reported by Martin
and co-workers in 2001.[7] This confirmed the absolute con-
figuration of hyacinthacine A2, proposed by Asano and co-
workers, as (1R,2R,3R,7aR)-1,2-dihydroxy-3-(hydroxy-
methyl)pyrrolizidine. Two quite similar syntheses with 1,3-
dipolar cycloaddition as the key reactions were reported by
Tamura[8] and Goti.[9] Izquierdo and co-workers prepared
a series of hyacinthacines by reductive cyclization of the
corresponding pyrrolidines.[10]
Previous work in our group has established a methodol-
ogy for the synthesis of cis-fused pyrrolizidines by olefin
cross metathesis (CM) followed by reductive amination.[11]
This strategy offers the potential to use the resulting C–C
double bonds in the CM product for further functionali-
zation. The synthetic strategy for hyacinthacine A2 was as
follows: as the synthetic precursor for the reductive cycliza-
tion we envisaged the diol 1, which would be prepared by
Sharpless asymmetric dihydroxylation of CM product 2, in
turn available from two simple building blocks, enantiopure
allyamine 3 and enone 4 (Scheme 1).
Introduction
3-(Hydroxymethyl)pyrrolizidines occupy a new class of
polyhydroxylated pyrrolizidines isolated from flowering and
leguminous plants.[1] The first examples of this family were
alexine, isolated in 1988 from Alexa leiopetala by Nash and
co-workers,[2] and australine, isolated in the same year from
the seeds of Castanospermum australe by Molyneux and co-
workers.[3] Recently, a series of hyacinthacines were isolated
from bluebells (Hyacinthoides non-scripta)[4] and grape hya-
cinths (Muscari armeniacum)[5] by Asano and co-workers
(Figure 1).
Figure 1. Various 3-(hydroxymethyl)pyrrolizidines.
As sugar mimics, many of these alkaloids possess gylcosi-
dase inhibition activity, which makes them potent drug can-
didates against viral infections, cancer, and diabetes.[6] Hya-
cinthacine A2, for example, was found to be a selective in-
hibitor of amyloglucosidase (Aspergillus niger) with an IC50
value of 8.6 µ.[5]
Scheme 1. Retrosynthetic analysis of hyacinthacine A2.
Results and Discussion
An expedient synthesis of enantiopure allylamine 3 uti-
lizing an enzymatic resolution of ( )-N-Cbz-vinylglycine
[a] Institut für Chemie, Technische Universität Berlin,
Strasse des 17. Juni 135, 10623 Berlin, Germany
Fax: +49-30-31423619
E-mail: blechert@chem.tu-berlin.de
1852
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1852–1856

Enantiospecific Synthesis of (+)-Hyacinthacine A2
FULL PAPER
methyl ester (5) has been established within our group.[12] after 3 days (Scheme 3). The high (E) selectivity of the CM
Successive esterification of 6, reduction of the ester group reaction was a great advantage for the subsequent Sharpless
by LiBH4, and protection of the hydroxy group as a TBS asymmetric dihydroxylation reaction.
ether gave allylamine (S)-3, as outlined in Scheme 2. The
optical rotation of the product {[α]2D0 = –31.2 (c = 1.2,
CH2Cl2)} was complementary to its known (R) counterpart
{ref.[12] [α]2D2 = +31.8 (c = 1.2, CH2Cl2)}.
The CM is slow, presumably because of the formation of
a six-membered chelate between ruthenium and the car-
bonyl oxygen of the Cbz group, as has also been observed
in CM of homoallyl esters or homoallyl amides.[18] The che-
lation effect slows down the metathesis activity and lowers
the catalytic turnover. Since CM is an intermolecular pro-
cess, chelation effects are more pronounced than in intra-
molecular reactions such as ring-closing metathesis.[18b] In
general, performing the reaction at elevated temperature (at
80 °C in toluene, for example) may increase the yield, but
in this case the decomposition of the catalyst proved to be
faster than the completion of the reaction.
We then investigated the dihydroxylation of enone 2. The
osmylation of electron-deficient olefins, such as α,β-unsatu-
rated carbonyl compounds, is very slow since osmium te-
troxide is an electrophilic reagent. The large TBS group
may play a role in controlling the diastereoselectivity (sub-
strate control), but it may also reduce the reaction rate by
the steric hindrance.
We first applied a dihydroxylation procedure under
acidic conditions (pH 4–6) with the use of citric acid and 4-
methylmorpholine.[19] After 6 days at room temp. the ex-
pected product and its diastereomer were isolated in a 1:2
ratio and a yield of 42%. We then applied a procedure de-
veloped for α,β-unsaturated ketones[20] under basic condi-
tions with potassium hexaferricyanide and a buffer system
(K2CO3/NaHCO3) in the absence of the chiral ligand to
study the substrate control. After 14 days, the expected diol
was isolated in 44% yield and with a de of 33%. These
results confirmed our assumption that the TBS group could
indeed exert moderate substrate control, dependent on the
reaction conditions, though simultaneously retarding the
reaction.
Scheme 2. Synthesis of CM partners.
Alkylation of lithiated methoxyallene[13] with commer-
cially available 2-(2-bromoethyl)-1,3-dioxolane yielded, af-
ter acidic workup, the enone 4, as shown in Scheme 2.[11]
According to TLC monitoring the alkylation reaction pro-
ceeded smoothly, but some allene intermediate decomposed
during the acidic workup, resulting in a moderate yield of
34%.
CM between allylamine 3 and enone 4 (1:2) was con-
ducted in dichloromethane at reflux in the presence of
10 mol-% Hoveyda–Blechert ruthenium catalyst [Ru].[14]
We then conducted the reaction with the use of AD-Mix-
This catalyst shows higher reactivity than the second-gener- β (Scheme 3). With addition of three equivalents of meth-
ation Grubbs’ catalyst[15] in reactions involving, for exam- anesulfonamide,[21] the expected diol was isolated in 42%
ple, fluorinated substrates[16] and acrylonitrile deriva- yield and with a de of 88% after 8 days at room temp. The
tives.[17] It also shows high stability towards water and oxy- best results were achieved with the use of excess AD-Mix-
gen and so can be stored under ambient atmosphere at β (2.1 g per mmol enone), methanesulfonamide (3.8 equiva-
room temp. The CM gave the (E) enone 2 in 73% yield lents), and K2OsO4 (with a total of 0.015 equivalents).[22]
Scheme 3. Synthesis of hyacinthacine A2 [IHMES = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene].
Eur. J. Org. Chem. 2006, 1852–1856
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1853

P. Dewi-Wülfing, S. Blechert
FULL PAPER
Scheme 4. Sequential double reductive cyclization.
Total conversion was achieved within one day, providing kylpyrrolizidine syntheses.[11] The IR spectrum supported
the diol 1 in 67% yield and with a de of 88%.
this, as no Bohlmann band was detected. The spectroscopic
The expected diol and its diastereomer were chromato- data and the optical rotation of the product {[α]2D0 = +11.2
graphically separable. The diastereoselectivity was deter- (c = 0.52, H2O)} were in agreement with the reported values
mined by H NMR and the diol configuration was deter- [ref.[7] [α]D25 = +12.5 (c = 0.6, H2O); ref.[9] [α]D25 = +12.7 (c =
1
mined by nOe experiments after cyclization.
0.13, H2O); ref.[10b] [α]D25 = +10.5 (c = 0.6, H2O)].
To cyclize the diol 1 we first applied the one-pot tandem
procedure, which had been successfully applied in the syn-
theses of cis-fused pyrrolizidines.[11] Unfortunately, these
attempts resulted in low yields and the formation of side
products. The first cyclization step occurred very slowly un-
der atmospheric pressure, and so it was decided to use a
higher pressure of hydrogen and neutral conditions. Once
the pyrrolidine intermediate had been formed, the protect-
ing group would be removed under acidic conditions, fol-
lowed by the second cyclization, reduction of the iminium
salt, and neutralization. The double reductive cyclization
was thus carried out sequentially, with the optimized pro-
cedure shown in Scheme 4.
Figure 2. Correlation observed in the nOe spectra of pyrrolidine 8
and hyacinthacine A2.
Conclusion
The first cyclization step was conducted at 4 bar hydro-
gen for 3 days at room temp. to give the pyrrolidine 8.[23]
Without isolation of the intermediate, hydrochloric acid
was added to cleave both the dioxolane and the TBS pro-
tecting groups, followed by the second cyclization to yield
the iminium salt 9. Hydrogenation of the iminium salt at
4 bar for 3 days afforded the hydrochloride salt of hya-
cinthacine A2 (10). Amberlite IRA 401 (OH– form) was
added to remove the chloride ions in the solution, followed
by addition of ammonia to remove the chloride ions
bonded to the product. The formation of a less polar prod-
uct and the disappearance of the polar salt could be moni-
In summary, we have described a concise synthesis of
(+)-hyacinthacine A2 in six steps, starting from (–)-N-Cbz-
vinylglycine, in an overall yield of 12%. The key steps of
our convergent synthesis were the highly stereoselective CM
reaction, diastereoselective Sharpless asymmetric dihydrox-
ylation, and the final sequential double reductive cycliza-
tion. Further syntheses based on this strategy are currently
underway and will be reported in due course.
Experimental Section
tored by TLC. The final purification by preparative TLC General Remarks: All moisture-sensitive reactions were conducted
under nitrogen in preheated glassware. Commercial reagents were
used without further purification. All solvents were purified and
dried prior to use. Thin-layer chromatography analysis (TLC) was
performed with silica gel 60 F254 precoated plates (0.2 mm thick-
ness) with fluorescent indicator. Components were detected by UV
(254 nm) and visualized with potassium permanganate reagent
(2.5% KMnO4 in 5% aqueous NaHCO3 solution). Preparative
TLC was conducted on silica-rapid plates (F254, 20×20 cm, 60 A)
from ICN Biomedicals. Column chromatography was performed
on silica gel (40–63 µm). Melting points were determined on a Le-
gave hyacinthacine A2 in 39% yield.
The configurations of pyrrolidine 8 and the final product
were determined by nOe experiments. The pyrrolidine 8
showed enhancements between H-2 and H-4 and between
H-3 and H-5, while the final product showed enhancements
of H-7a with H-2, H-1 with H-3 and H-7, and H-3 with H-
5, consistently with the reported structure of hyacintha-
cine A2 (Figure 2). This also confirmed the diol configura-
tion and the cis-fused configuration of the product, which
was in accordance with our previous results for 3,5-dial- ica–Galen melting point microscope with a Wagner–Munz control
1854 Eur. J. Org. Chem. 2006, 1852–1856
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Enantiospecific Synthesis of (+)-Hyacinthacine A2
FULL PAPER
1
module and are uncorrected. The H and 13C NMR spectra were
0.08 (s, 6 H, SiMe2), 0.90 (s, 9 H, tBu), 3.55–3.80 (m, 2 H, 1-H),
4.25 (br.s, 1 H, 2-H), 5.10 (s, 2 H, CH2Ph), 5.10 (m, 1 H, 4-H),
5.23 (d, J = 17.5 Hz, 1 H, 4-H), 5.85 (ddd, J = 17.5, 10.5, and
5.5 Hz, 1 H, 3-H), 7.45 (m, 5 H, Ar) ppm. 13C NMR (50 MHz,
CDCl3): δ = –5.6 (SiMe2), 18.2 (Si–C), 25.7 [(CH3)3C], 54.6 (CHN),
65.1 (CH2O), 66.6 (CH2Ar), 115.8 (CH2 = CH), 128.4 (Ar), 128.4
(Ar), 136.1 (CH2 = CH), 136.4 (Ar), 155.8 (CO) ppm. MS (EI,
25 °C): m/z (%) = 278 [M – C4H9]+ (62%), 243 (72), 234 (75), 200
(65), 165 (43), 149 (70), 91 (100).
recorded at room temp. with Bruker spectrometers and the chemi-
cal shifts are referenced to the internal solvent peaks (CDCl3 or
D2O) in ppm. The IR spectra were obtained as ATR (Attenuated
Total Reflectance) on a Perkin–Elmer 881 spectrometer. MS and
HRMS spectra were measured with a Finnigan MAT 95 SQ or
Varian MAT 711 by EI (electron ionization) and FAB (fast atom
bombardment) methods at 70 eV. The optical rotations were re-
corded on a Perkin–Elmer 341 polarimeter at 20 °C, with use of
the sodium -line at 589 nm, and are given as [α]D values (concen-
tration in grams/100 mL of solvent).
5-(1,3-Dioxolan-2-yl)pent-1-en-3-one (4): Methoxyallene (643 mg,
9 mmol) was dissolved in anhydrous THF (8 mL) and the solution
was cooled to –35 °C. n-BuLi (5.5 mL, 9 mmol, 1.6  in hexane)
was added dropwise. After the system had been stirred for 1 h at
the same temperature, 2-(2-bromoethyl)-1,3-dioxolane (0.83 g,
4.6 mmol) in anhydrous THF (4 mL) was added. The mixture was
warmed to 0 °C while stirring for 3 h and hydrolyzed by addition
of aqueous HCl solution (1 , 15 mL) and stirring at 0 °C for
10 min. The mixture was extracted with diethyl ether (3×20 mL).
The combined organic layers were dried with MgSO4 and carefully
evaporated under reduced pressure (until 400 mbar). Purification
Methyl (S)-2-(Benzyloxycarbonylamino)but-3-enoate: Thionyl chlo-
ride (0.37 mL, 5.1 mmol) was added slowly to anhydrous methanol
(4 mL) at 0 °C. After the system had been stirred for 15 min, -
Cbz-vinylglycine (6) (1 g, 4.2 mmol) was added in small portions
and the mixture was allowed to warm to room temp. overnight.
Water (5 mL) was added and the mixture was extracted with
MTBE (4×10 mL). The combined organic layers were dried with
MgSO4 and the solvents were evaporated. Purification by column
chromatography (SiO2, hexane/ethyl acetate, 9:1) gave the methyl
ester (996 mg, 94%) as a clear oil. RF = 0.71 (SiO2, hexane/ethyl by flash column chromatography (SiO2, diethyl ether/pentane, 1:1)
acetate, 3:2). [α]2D0 = –8.9 (c = 0.82, MeOH) {ref.[24] [α]2D0 = –8.86 (c
gave enone 4 (246 mg, 34%) as a yellow oil, which was stored as
1  solution in anhydrous CH2Cl2 at –20 °C. RF = 0.37 (SiO2, di-
1
= 1.84, MeOH)}. H NMR (400 MHz, CDCl3): δ = 3.77 (s, 3 H,
CO2Me), 4.86–4.98 (m, 1 H, 2-H), 5.13 (s, 2 H, CH2Ph), 5.28 (dd, ethyl ether/pentane, 1:1). 1H NMR (500 MHz, CDCl3): δ = 2.01
J = 10.5 and 1.5 Hz, 1 H, 4-H), 5.37 (dd, J = 17.5 and 1.5 Hz, 1
(dt, J = 7.2 and 4.4 Hz, 2 H, 5-H), 2.72 (t, J = 7.5 Hz, 2 H, 4-H),
H, 4-H), 5.46 (br.d, J = 7.5 Hz, 1 H, NH), 5.91 (ddd, J = 17.5, 3.83–4.00 (m, 4 H, 7, 8-H), 4.93 (t, J = 4.4 Hz, 6-H), 5.83 (dd, J =
10.5, and 5.5 Hz, 1 H, 3-H), 7.29–7.41 (m, 5 H, Ar) ppm. 13C NMR 10.5 and 0.9 Hz, 1 H, 1-H), 6.23 (dd, J = 17.7 and 0.8 Hz, 1 H, 1-
(125 MHz, CDCl3): δ = 52.4 (CO2CH3), 56.0 (C-2), 66.9 (CH2Ph), H), 6.36 (dd, J = 17.6 and 10.5 Hz, 1 H, 2-H) ppm. 13C NMR
117.6 (C-4), 127.9, 128.0 (Ar), 132.1 (C-3), 136.0 (Ar), 155.4
(125 MHz, CDCl3): δ = 27.7 (C-5), 33.4 (C-4), 65.0 (C-7, 8), 103.4
(NCO), 170.7 (C-1) ppm.
(C-6), 128.1 (C-1), 136.2 (C-2), 199.9 (C-3) ppm. IR (ATR): ν =
˜
1713, 1139, 1032 cm–1. MS (EI, 25 °C): m/z (%) = 155 [M – H]+
(3%), 73 (100). HRMS ([M – H], C8H11O3): calcd. 155.0708, found
155.0710.
Benzyl (S)-[1-(Hydroxymethyl)allyl]carbamate: Anhydrous meth-
anol (0.13 mL) and methyl (S)-2-(benzyloxycarbonylamino)but-3-
enoate (411 mg, 1.7 mmol) in anhydrous diethyl ether (5 mL) were
added successively to a suspension of LiBH4 (72 mg, 3.3 mmol) in
anhydrous diethyl ether (7 mL) and the mixture was stirred at room
temp. for 2 h. Water (5 mL) was added and the mixture was ex-
tracted with MTBE (3×15 mL). The combined organic layers were
Benzyl [(E)-(S)-1-(tert-Butyldimethylsilanyloxymethyl)-6-(1,3-diox-
olan-2-yl)-4-oxo-hex-2-enyl]carbamate (2): [1,3-Bis(2,4,6-trimeth-
ylphenyl)-2-imidazolidinylidene]dichloro(o-isopropoxyphenylmeth-
ylene)ruthenium ([Ru], 10 mg, 16 µmol) was added to a solution of
dried with MgSO4 and the solvents were evaporated. Purification allylamine 3 (54 mg, 0.16 mmol) and enone 4 (0.16 mL, 0.16 mmol,
by column chromatography (SiO2, hexane/ethyl acetate, 3:2) gave
the alcohol (285 mg, 78%) as a white solid. RF = 0.24 (SiO2, hex-
ane/ethyl acetate, 3:2). M.p. 47–48 °C. [α]2D0 = –27.4 (c = 1.54,
CHCl3) {ref.[25] [α]2D0 = –32.2 (c = 1.46, CHCl3)}.1H NMR
(400 MHz, CDCl3): δ = 1.92 (br.s, 1 H, OH), 3.65–3.78 (m, 2 H,
1  solution in anhydrous CH2Cl2) in anhydrous CH2Cl2 (3.2 mL)
under nitrogen. The mixture was then heated at reflux for 3 days.
The solvent was evaporated and the residue was purified by column
chromatography (SiO2, hexane/ethyl acetate, 3:1) to give ene-dione
2 (54 mg, 73%) as a yellow oil. RF = 0.6 (SiO2, hexane/ethyl acetate,
1-H), 4.34 (s, 1 H, 2-H), 5.13 (br.s, 3 H, CH2Ph, NH), 5.21–5.34 3:2). [α]2D0 = –0.53 (c = 0.95, CHCl3). 1H NMR (500 MHz, CDCl3):
(m, 2 H, 4-H), 5.91 (ddd, J = 17.5, 10.5, and 5.5 Hz, 1 H, 3-H), δ = 0.03 (s, 6 H, SiMe2), 0.85 (s, 9 H, tBu), 1.99 (dt, J = 7.0 and
7.30–7.41 (m, 5 H, Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = 4.0 Hz, 2 H, 7-H), 2.65 (m, 2 H, 6-H), 3.63–3.76 (m, 2 H, 2-H),
54.9 (C-2), 64.5 (CH2Ph), 66.8 (C-1), 116.4 (C-4), 127.9, 128.0,
128.4 (Ar), 135.1 (C-3), 136.2 (Ar), 156.4 (NCO) ppm. MS (EI,
70 °C): m/z (%) = 278 [M]+ (2%), 91 (100).
3.77–4.00 (m, 4 H, 9, 10-H), 4.40 (m, 1 H, 2-H), 4.90 (s, 1 H, 9-
H), 5.10 (s, 2 H, 12-H), 5.19 (br.s, 1 H, NH), 6.23 (d, J = 16.0 Hz,
1 H, 4-H), 6.75 (dd, J = 16.0 and 4.0 Hz, 1 H, 3-H), 7.32 (m, 5 H,
Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = –5.4 (SiMe2), 18.3 (Si–
C), 25.9 [(CH3)3C], 27.7 (C-7), 34.4 (C-6), 53.7 (C-1), 64.7 (C-2),
65.0 (C-9, 10), 67.1 (CH2Ph), 103.4 (C-8), 128.3, 128.6 (Ar), 130.2
(C-4), 136.3 (Ar), 143.6 (C-3), 155.8 (CO2), 198.9 (C-5) ppm. IR
Benzyl
(3): tert-Butylchlorodimethylsilane (233 mg, 1.55 mmol) was added
to solution of benzyl (S)-[1-(hydroxymethyl)allyl]carbamate
(S)-[1-(tert-Butyldimethylsilanyoxymethyl)allyl]carbamate
a
(285 mg, 1.3 mmol) in anhydrous DMF (2 mL) and the mixture
was stirred at 0 °C for 10 min. Imidazole (219 mg, 3.22 mmol) was
added portionwise and the reaction mixture was further stirred at
0 °C for 3 min and at room temp. for 18 h. MTBE was added and
the mixture was washed with aqueous NaHCO3 solution (10%).
The organic phase was dried with MgSO4 and the solvents were
evaporated. Purification by column chromatography (SiO2, hexane/
(ATR): ν = 1723, 1701, 1678, 1636, 1253, 1111, 980 cm–1. MS (EI,
˜
120 °C): m/z (%) = 463 [M]+ (2%), 91 (100), 73 (32). HRMS
([M]+, C24H37O6NSi): calcd. 463.2390, found 463.2381. CHN-
analysis (C24H37NO6Si): calcd. C 62.17, H 8.05, N 3.02; found C
62.04, H 7.95, N 3.15.
Benzyl [(1R,2R,3S)-1-(tert-Butyldimethylsilanyloxymethyl)-6-(1,3-
ethyl acetate, 9:1) gave 3 (405 mg, 88%) as a white solid. RF = 0.15 dioxolan-2-yl)-2,3-dihydroxy-4-oxo-hexyl]carbamate (1): AD-Mix-β
(SiO2, hexane/ethyl acetate, 3:2). M.p. 60–61 °C (ref.[12] 59–61 °C).
(768 mg), NaHCO3 (97 mg), MeSO2NH2 (138 mg), and
K2OsO4·2H2O (1.5 mg) were dissolved in tert-butyl alcohol/water
1
[α]2D0 = –31.2 (c = 1.2, CH2Cl2). H NMR (200 MHz, CDCl3): δ =
Eur. J. Org. Chem. 2006, 1852–1856
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P. Dewi-Wülfing, S. Blechert
FULL PAPER
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(1:1, 1.8 mL) and stirred for 10 min. CM product 2 (169 mg,
0.36 mmol) in tert-butyl alcohol/water (1:1, 1.8 mL) was added and
the mixture was stirred at room temp. for 18 h. Na2SO3 (700 mg)
and water (1 mL) were added, and the mixture was stirred for a
further 1 h and extracted with ethyl acetate (3×10 mL). The com-
bined organic layers were washed sequentially with aqueous NaOH
solution (1 , 2×10 mL), water (2×10 mL), and brine, and dried
with MgSO4, and the solvents were evaporated. Purification by col-
umn chromatography (SiO2, hexane/ethyl acetate, 3:1 Ǟ 3:2) gave
the diol 1 and its diastereomer (isolated yield 122 mg with 115 mg
diol 1, 67% yield) as a clear oil. RF = 0.2 (SiO2, hexane/ethyl ace-
tate, 3:2). [α]2D0 = –10.1 (c = 0.9, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 0.05 (s, 6 H, SiMe2), 0.86 (s, 9 H, tBu), 1.20–1.29 (m,
1 H, OH), 1.96–2.09 (m, 2 H, 7-H), 2.55–2.82 (m, 2 H, 6-H), 3.70
(dd, J = 10.3 and 5.1 Hz, 1 H, 1-H), 3.74–4.00 (m, 5 H, 2, 9, 10-
H), 4.05 (dd, J = 10.3 and 2.6 Hz, 1 H, 1-H), 4.10 (t, J = 9.0 Hz,
1 H, 3-H), 4.19 (dd, J = 19.4 and 3.6 Hz, 1 H, 4-H), 4.92 (m, 1 H,
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Watson, Mini-Rev. Med. Chem. 2001, 1, 145–154; e) N. Asano,
R. J. Nash, R. J. Molyneux, G. W. J. Fleet, Tetrahedron: Asym-
metry 2000, 11, 1645–1680.
8-H), 5.10 (br.s, 2 H, CH2Ph), 5.54 (d, J = 8.5 Hz, 1 H, NH), 7.34 [7] L. Rambaud, P. Compain, O. R. Martin, Tetrahedron: Asym-
(m, 5 H, Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = –5.5 (SiMe2),
18.3 (Si–C), 25.9 [(CH3)3C], 27.2 (C-7), 32.5 (C-6), 54.1 (C-2), 62.1
(C-1), 65.1 (C-9, 10), 67.3 (CH2Ph), 70.7 (C-3), 76.9 (C-4), 103.2
(C-8), 128.3, 128.7, 136.1 (Ar), 157.1 (CO2), 210.4 (C-5) ppm. IR
metry 2001, 12, 1807–1809.
[8] A. Toyao, O. Tamura, H. Takagi, H. Ishibashi, Synlett 2003,
1, 35–38.
[9] F. Cardona, E. Faggi, F. Liguori, M. Cacciarini, A. Goti, Tetra-
hedron Lett. 2003, 44, 2315–2318.
(ATR): ν = 1715, 1509, 1254, 1087, 1046, 779 cm–1. MS (EI,
˜
[10] a) I. Izquierdo, M. T. Plaza, F. Franco, Tetrahedron: Asym-
metry 2004, 15, 1465–1469; b) I. Izquierdo, M. T. Plaza, F.
Franco, Tetrahedron: Asymmetry 2003, 14, 3933–3935; c) I. Iz-
quierdo, M. T. Plaza, F. Franco, Tetrahedron: Asymmetry 2002,
13, 1581–1585; d) I. Izquierdo, M. T. Plaza, R. Robles, F.
Franco, Tetrahedron: Asymmetry 2001, 12, 2481–2487.
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43–46.
130 °C): m/z (%) = 496 [M – H]+ (Ͻ1%), 91 (100). HRMS ([M –
H], C24H38NO8Si): calcd. 496.2367, found 496.2379.
Data for the Diastereomer of Diol 1: RF = 0.14 (SiO2, hexane/ethyl
1
acetate, 3:2). [α]2D0 = –22.3 (c = 0.4, CHCl3). H NMR (500 MHz,
CDCl3): δ = 0.05 (s, 6 H, SiMe2), 0.85 (s, 9 H, tBu), 1.22–1.32 (m,
1 H, OH), 1.94–2.07 (m, 2 H, 7-H), 2.55–2.82 (m, 2 H, 6-H), 3.70–
4.00 (m, 7 H, 1, 2, 9, 10-H), 4.20 (br.s, 2 H, 3, 4-H), 4.90 (m, 1 H,
8-H), 5.10 (br.s, 2 H, CH2Ph), 5.35 (d, J = 8.5 Hz, 1 H, NH), 7.30
[12] a) C. Huwe, S. Blechert, Synthesis 1997, 61–67; b) C. Huwe,
Dissertation, Berlin, University of Technology, 1996, p. 13.
(m, 5 H, Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = –5.5 (SiMe2), [13] R. Zimmer, Synthesis 1993, 165–178.
[14] a) S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J.
18.2 (Si–C), 25.9 [(CH3)3C], 27.4 (C-7), 32.3 (C-6), 54.0 (C-2), 63.9
(C-1), 65.0 (C-9, 10), 67.3 (CH2Ph), 72.5 (C-3), 76.9 (C-4), 103.0
(C-8), 128.3, 128.6, 136.3 (Ar), 176.6 (CO2), 209.3 (C-5) ppm.
Am. Chem. Soc. 2000, 122, 8168–8179; b) S. Gessler, S. Randl,
S. Blechert, Tetrahedron Lett. 2000, 41, 9973–9976.
[15] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999,
1, 953–956.
(+)-Hyacinthacine A2: Diol
1 (30 mg, 60 µmol) in methanol
(10 mL) was hydrogenated at 4 bar over Pd/C (10%, 7 mg, 6 µmol)
for 3 days. TLC analysis showed that the first cyclization had oc-
curred [RF = 0.47 (SiO2, MeOH)]. Concentrated HCl (3 drops)
was then added and the mixture was further stirred at room temp.
overnight. The heterogeneous mixture was again hydrogenated at
4 bar for 3 days. After filtration through celite, the filtrate was neu-
tralized with Amberlite IRA 401 (wet, OH– form). After filtration
and evaporation, the residue containing the HCl salt was dissolved
in methanol (5 mL), and ammonia (6 drops) was added. The mix-
ture was stirred for 30 min, concentrated, and purified by prepara-
tive TLC (SiO2, methanol/ammonia 98:2) to give the hyacinthac-
ine A2 (4 mg, 39%) as a yellow oil. RF = 0.14 (SiO2, methanol).
[α]2D0 = +11.2 (c = 0.52, H2O). 1H NMR (500 MHz, CDCl3): δ =
1.49–1.61 (m, 2 H, 6, 7-H), 1.62–1.69 (m, 1 H, 6-H), 1.69–1.75 (m,
1 H, 7-H), 2.46–2.49 (m, 1 H, 3-H), 2.49–2.57 and 2.64–2.42 (m, 1
H, 5-H), 2.90–2.96 (m, 1 H, 7a-H), 3.40–3.47 (dd, J = 11.0 and
6.8 Hz, 1 H, 8-H), 3.62 (br.t, J = 8.0 Hz, 1 H, 1-H), 3.54–3.61 (m,
2 H, 2, 8-H) ppm. 13C NMR (125 MHz, D2O): δ = 25.2 (C-6), 30.5
(C-7), 55.6 (C-5), 63.8 (C-8), 66.7 (C-7a), 69.9 (C-3), 78.0 (C-2),
[16] S. Imhof, S. Randl, S. Blechert, Chem. Commun. 2001, 1692–
1693.
[17] S. Randl, S. Gessler, H. Wakamatsu, S. Blechert, Synlett 2001,
3, 430–432.
[18] a) A. Furstner, O. R. Thiel, C. W. Lehmann, Organometallics
2002, 21, 331–335; b) T. Choi, A. Chatterjee, R. H. Grubbs,
Angew. Chem. Int. Ed. 2001, 113, 1317–1319.
[19] P. Dupau, R. Epple, A. A. Thomas, V. V. Fokin, K. B.
Sharpless, Adv. Synth. Catal. 2002, 344, 421–433.
[20] P. Walsh, K. B. Sharpless, Synlett 1993, 605–606.
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Chem. Soc. 2002, 124, 12420–12421.
[22] H. Ishiyama, T. Takemura, M. Tsuda, J. Kobayashi, J. Chem.
Soc., Perkin Trans. 1 1999, 1163–1166.
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4809–4812.
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Bull. 1994, 42, 1927–1930.
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Received: November 23, 2005
Published Online: February 21, 2006
80.9 (C-1) ppm. IR (ATR): ν = 3313, 2922, 2868, 1115, 1040 cm–1.
˜
MS (FAB): m/z (%) = 174 [M + H]+ (100%).
[1] Recent review: S. G. Pyne, M. Tang, Curr. Org. Chem. 2005, 9,
1393–1418.
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