An Asymmetric Total Synthesis of Broussonetine C

Article abstract of DOI:10.1081/CAR-120026470

A total synthesis of (+) Broussonetine C in 16 steps is described from D-arabinose.

Full text of DOI:10.1081/CAR-120026470

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An Asymmetric Total Synthesis of Broussonetine C
Patrick Perlmutter a & Filisaty Vounatsos a
a School of Chemistry , Monash University , P.O. Box 23, Victoria, 3800, Australia
Published online: 23 Feb 2007.
To cite this article: Patrick Perlmutter & Filisaty Vounatsos (2003) An Asymmetric Total Synthesis of Broussonetine C , Journal
of Carbohydrate Chemistry, 22:7-8, 719-732, DOI: 10.1081/CAR-120026470
To link to this article: http://dx.doi.org/10.1081/CAR-120026470
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, Nos. 7 & 8, pp. 719–732, 2003
An Asymmetric Total Synthesis of Broussonetine Cy
*
Patrick Perlmutter and Filisaty Vounatsos
School of Chemistry, Monash University, Victoria, Australia
ABSTRACT
A total synthesis of (+) Broussonetine C in 16 steps is described from D-arabinose.
Key Words: Broussonetine; Grignard; Azide; Staudinger; Mitsunobu; Cyclisation.
INTRODUCTION
Broussonetine C, a member of the Broussonetia class, was first isolated from the
branches of Broussonetia Kazinoki (a deciduous tree distributed throughout Japan,
China and Taiwan) in 1997 by Kusano et al.[1,2] and was assigned structure 1. All of
the Broussonetines incorporate a 2,3,4,5-tetrasubstituted pyrrolidine unit as a key motif,
probably the most synthetically challenging substructure associated with this class of
natural product. Significantly, Broussonetine C was found to exhibit unique b-galac-
tosidase and b-mannosidase activities.[1,2] Such properties, coupled with the unique
structure assigned to the alkaloid encouraged us to choose 1 as a novel synthetic target.
Thus far, only one asymmetric total synthesis of this pyrrolidine alkaloid has been
reported.[3] In this report we describe a synthesis of 1, starting from D-arabinose.
yThis paper is dedicated to Professor Ge´rard Descotes on the occasion of his 70th birthday.
*
Correspondence: Patrick Perlmutter, School of Chemistry, Monash University, P.O. Box 23,
Victoria 3800, Australia; Fax: (+613) 9905-4597; E-mail: Patrick.Perlmutter @sci.monash.edu.au.
719
DOI: 10.1081/CAR-120026470
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

720
Perlmutter and Vounatsos
DISCUSSION
Initial studies focused on the construction of the intermediate 5, as it was anti-
cipated that 5 could be assembled via addition of undecenylmagnesium bromide[4] to 4.
The latter was prepared from the dithioacetal intermediate 3 obtained upon silylation of
the known 2,3-di-O-benzyl-D-arabinose diethyl dithioacetal[5] 2 (Scheme 1). Grignard[6]
addition of undecenylmagnesium bromide to lactol 4 provided 5 contaminated with less
than 5% of its chromatographically separable diastereomer. Purified 5 (80%) was then
Scheme 1. (i) TBSCl, Imidazole, DMF, rt, 12 h; (ii) HgO, HgCl2, acetone/water (10:1), 60 °C,
3 h; (iii) undecenylmagnesium bromide, THF, rt, 3 h; (iv) HCl (2M solution in MeOH), 0 °C, 3 h;
(v) benzaldehyde dimethyl acetal, p-TsOH (catalytic), CH2Cl2, ꢀ20 °C to rt, 2 h; (vi) Et3N,
MsCl, CH2Cl2, 0 °C to rt, 1.5 h; (vii) NaN3, DMF, 60 °C, 18 h; (viii) AlCl3, BH3.NMe3, THF, 0 °C
to rt, 3 h; (ix) DEAD, PPh3, p-nitrobenzoic acid, THF, 18 h, rt.

Asymmetric Total Synthesis of Broussonetine C
721
smoothly desilylated with methanolic HCl and transformed into the corresponding
benzylidene acetal 7 by reaction with benzaldehyde dimethyl acetal (BDMA) in the
presence of p-toluenesulfonic acid (p-TsOH).
Introduction of nitrogen at C5 required activation and inversion of the hydroxyl
group in the precursor 7. This was effected by treatment of 7 with methanesulfonyl
chloride (MsCl) in the presence of Et3N. The resulting product 8 was immediately
treated with NaN3 in DMF providing azide 9 as a single isomer in 82% yield.[7]
Regioselective opening[8] of the benzylidene acetal 9 using AlCl3, BH3.NMe3 in THF
delivered 10 in 67% yield.
Mitsunobu inversion[9] of the free hydroxyl group in 10 with p-nitrobenzoic acid as
the nucleophilic species afforded 11. Subsequent Staudinger reduction[10] of the azide
moiety under neutral conditions [using PPh3:H2O (1:1) in THF at reflux] gave 12 in
quantitative yield. Methanolysis followed by treatment of 13 with Et3N, (Boc)2O in
THF (Scheme 2) provided the pivotal cyclisation precursor 14 (61% over two steps).
Mesylation of 14 was achieved under standard conditions and the product 15 was
immediately treated with potassium tert-butoxide (t-BuOK).[11] In this way mesylate 15
underwent intramolecular cyclisation with the secondary amide and concomitant
inversion at C2 to give 16, in which all the stereocenters have the correct configuration
for the natural product (90% over two steps).
Dihydroxylation[12] of 16 followed by oxidative cleavage of the diol in 17 yielded
aldehyde 18 (Scheme 3). Aldehyde 18 was immediately treated with benzyloxypropyl-
magnesium bromide[13] and the resulting mixture of diastereomeric alcohols 19 (70%)
was oxidized to the corresponding ketone 20 (98%) using Dess-Martin periodinane.[14]
Completion of the synthesis of Broussonetine C (1) (Scheme 3) was achieved by
hydrogenolysis of the benzyl ethers using palladium on carbon under an atmosphere
of hydrogen, followed by hydrolysis with TFA in THF. The 1H and 13C NMR
spectroscopic data for synthetic 1 were identical to those of the natural product and
Scheme 2. (i) PPh3:H2O (1:1), THF, 60 °C, 4 h; (ii) NaOH, methanol, rt, 1 h; (iii) Et3N, (Boc)2O,
THF, rt, 3 h; (iv) Et3N, MsCl, CH2Cl2, 0 °C to rt, 1.5 h; (v) t-BuOK, THF, 8 h.

722
Perlmutter and Vounatsos
Scheme 3. (i) K2OsO4.2H2O, NMO, acetone:H2O (1:1), rt, 3 h; (ii) NaIO4, Et2O:H2O (1:1), rt, 2
h; (iii) benzyloxypropylmagnesium bromide, THF, 0 °C to rt, 3 h; (iv) Dess-Martin reagent,
CH2Cl2, 0 °C to rt, 2 h; (v) Pd/C, 5% AcOH in MeOH, H2, 18 h; (vi) Trifluroacetic acid in THF,
the specific rotation {[a]D + 32 (c 0.40, MeOH) } was comparable to that of the natural
product.[1,2]
EXPERIMENTAL
General Procedures. Unless otherwise specified, proton (1H) and carbon (13C)
NMR spectra were recorded on a Varian Mercury 300 spectrometer operating at 300

Asymmetric Total Synthesis of Broussonetine C
723
MHz for proton and 75 MHz for carbon nuclei. Chemical shifts were recorded as d
values in parts per million (ppm). Spectra were acquired in deuterochloroform (CDCl3)
1
at 20°C unless otherwise stated. For H NMR spectra recorded in CDCl3, the peak due
to residual CHCl3 (d 7.26) was used as the internal reference. 1H NMR data are
recorded as follows: chemical shift (d) [multiplicity, coupling constant(s) J (Hz), rel-
ative integral, assignment (where possible)] where multiplicity is defined as: s = singlet;
d = doublet; t = triplet; q = quartet; m = multiplet or combinations of the above. The
central peak (d 77.0) of the CDCl3 triplet was used as the reference for proton-decoupled 13
C
NMR spectra. For 13C NMR spectra, the data are given as: chemical shift (d) (protonicity),
where protonicity is defined as: C = quaternary; CH = methine; CH2 = methylene; CH3 =
methyl; C or CH2 = quaternary or methylene; CH or CH3 = methine or methyl. The
assignments of signals observed in various NMR spectra were often assisted by conducting
attached proton test (APT) and homonuclear (1H/1H) correlation spectroscopy (COSY)
experiments. Infrared spectra (nmax) were recorded on a Perkin-Elmer 1600 Fourier
Transform Infrared Spectrophotometer. Samples were analysed as thin films on NaCl
plates (for liquids/oils). High resolution mass spectra (HRMS) for accurate mass
determinations were recorded on a Bruker BioApex 47e FTMS fitted with an analytical
electrospray source using NaI for accurate mass calibration. The principal ion peaks (m/z)
are reported along with their intensities, expressed as a percentage of the base peak
(100%). M+ refers to the molecular ion. Optical rotations were measured with a PolAAr
2001 automatic polarimeter at the sodium D-line (589 nm) using the spectroscopic grade
solvents specified at 20°C and at the concentrations (c) (g/100 mL) indicated. The
measurements were carried out in a cell with a path length of 1 dm. Specific rotations
{[a]D20} were calculated using the equation [a]D = (100.a)/(c.l) and are given in
10ꢀ1.deg.cm2.gꢀ1. Analytical thin-layer chromatography (TLC) was conducted on
Polygram Sil G/UV254 and the chromatograms were visualised under a 254 nm UV lamp
and/or by treatment with an ammonium molybdate/ cerium sulfate solution followed by
heating. Flash chromatography was conducted using silica gel 60 (mesh size 0.040–
0.063 mm) as the stationary phase and the analytical reagent (AR) grade solvents
indicated. Many starting materials and reagents were available from the Aldrich
Chemical Company and were used as supplied or simply distilled. Drying agents and
other inorganic salts were purchased from AJAX or BDH Chemicals. Reactions
employing air-and/or moisture-sensitive reagents and intermediates were carried out
under an atmosphere of dry, oxygen-free nitrogen in flame-dried apparatus.
Tetrahydrofuran (THF) and diethyl ether were dried using sodium metal and then
distilled, as required, from sodium benzophenone ketyl. Dichloromethane (CH2Cl2) was
distilled from calcium hydride. N,N-dimethylformamide (DMF) was heated at reflux
˚
over calcium hydride for 16 h then distilled and stored over 3 A molecular sieves.
Organic solutions obtained from work-up of reaction mixtures were dried with
magnesium sulfate (MgSO4). Hexane refers to the hydrocarbon fraction boiling in
the range 40–60°C unless otherwise specified. Organic solutions were concentrated
under reduced pressure on a rotary evaporator with the water bath generally not ex-
ceeding 40°C.
2,3-Bis-phenylmethyloxy-5-[(1,1-dimethylethyl)dimethylsilyloxy]-D-arabinose
(3). tert-Butyldimethylsilyl chloride (8.42 g, 54.50 mmol) was added to a magnet-
ically stirred solution of 2,3-di-O-benzyl-D-arabinose diethyl dithioacetal (2), (20 g,

724
Perlmutter and Vounatsos
45.42 mmol) and imidazole (4.02 g, 59.05 mmol) in anhydrous DMF (100 mL) main-
tained at rt under an atmosphere of nitrogen. After 12 h the reaction mixture was poured
into water (500 mL) and extracted with CH2Cl2 (3 ꢁ 250 mL). The combined organic
phases were washed with water (500 mL) and brine (400 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to afford a light yellow oil.
Flash chromatography (5%–25% v/v ethyl acetate/hexane elution) gave compound 3
1
(21.9 g, 87%) as a yellow oil: [a]D + 17.7 (c 0.72, CHCl3); H NMR (300 MHz) d
7.38–7.25 (m, 10H), 4.90 (d, J = 11.0 Hz, 1H), 4.78 (d, J = 11.0 Hz, 1H), 4.77 (d,
J = 11.4 Hz, 1H), 4.64 (d, J = 11.4 Hz, 1H), 4.18 (d, J = 6.3 Hz, 1H), 4.00 (m, 2H),
3.80 (m, 2H), 3.67 (m, 1H), 2.67 (m, 4H), 1.24 (m, 6H), 0.91 (s, 9H), 0.07 (s, 3H), 0.06
(s, 3H); 13C NMR (75 MHz) d 138.3 (C), 138.2 (C), 128.5 (2 ꢁ CH, coincident), 128.4
(2 ꢁ CH, coincident), 128.2 (2 ꢁ CH, coincident), 128.1 (2 ꢁ CH, coincident), 127.8
(CH), 127.7 (CH), 82.8 (CH), 79.3 (CH), 75.3 (CH2), 74.5 (CH2), 71.9 (CH2), 64.3
(CH2), 53.7 (CH), 26.2 (3 ꢁ CH3, coincident), 26.1 (2 ꢁ CH2, coincident), 25.2 (C),
14.8 (2 ꢁ CH3, coincident), ꢀ4.9 (2 ꢁ CH3, coincident); IR nmax 3540, 3031, 2928,
2856, 1497, 1454, 1255, 1097, 1028, 836 cmꢀ1; HRMS Calcd for C29H46O4S2Si:
[M + Na]+ m/z 573.2504. Found 573.2495.
(2R,3R,4R,5S)-1-[(1,1-Dimethylethyl)dimethylsilyloxy]-3,4-bis(phenylmethyl-
oxy)hexadec-15-ene-2,5-diol (5). Compound 3 (21 g, 36 mmol) was dissolved in
acetone/water (60 mL of a 10:1 solution) and HgO (19.4 g, 88.36 mmol) was added
in one portion, followed by HgCl2 (10.95 g, 40.34 mmol). The reaction mixture was
heated to 60°C for 3 h, then filtered through a bed of CeliteTM. The solvent was con-
centrated under reduced pressure and the residue was diluted with CH2Cl2 (150 mL),
then washed with potassium iodide (3 ꢁ 100 mL of a 1M aq solution) and brine
(1 ꢁ 200 mL), before being dried (MgSO4), filtered and concentrated under reduced
pressure to afford 2,3-di-O-benzyl-5-O-tert-butyldimethylsilyl-D-arabinose (4) as a pale
yellow oil. This material was used, without purification, in the next step of the reaction
sequence. Undecenylmagnesium bromide (364 mL of a 0.1 M solution in THF, 0.36 mol)
was added, dropwise, to neat lactol 4 (18 g, 40.38 mmol) maintained at 20°C under a
nitrogen atmosphere. The reaction mixture was stirred at rt for 3 h, then treated with
NH4Cl (500 mL of a saturated aq solution). The mixture thus obtained was partitioned
between diethyl ether (3 ꢁ 500 mL) and the combined organic phases were washed with
brine (1 ꢁ 500 mL) before being dried (MgSO4), filtered and concentrated under
reduced pressure to afford a pale yellow oil. Flash chromatography (0%–25% v/v ethyl
acetate-hexane elution) gave 5 (19.3 g, 80%) as a clear colourless oil: [a]D + 7 (c 0.4,
CHCl3); 1H NMR (300 MHz) d 7.38–7.25 (m, 10H), 5.80 (m, 1H), 5.03ꢀ4.90 (complex
m, 2H), 4.79 (d, J = 11.2 Hz, 1H), 4.62 (d, J = 7 Hz, 2H), 4.58 (d, J = 11.3 Hz, 1H),
3.87 (m, 1H), 3.81 (d, J = 3.7 Hz, 1H), 3.78 (d, J = 3.3 Hz, IH), 3.72 (m, 2H), 3.56 (t,
J = 4.1 Hz, 1H), 2.93 (br s, 1H), 2.65 (br s, 1H), 2.02 (app. q, J = 6.8 Hz, 2H), 1.30 (m,
18H), 0.88 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz) d 139.4 (CH), 138.3
(C), 138.2 (C), 128.6 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.2 (2 ꢁ CH,
coincident), 128.1 (CH), 128.0 (2 ꢁ CH, coincident), 127.9 (CH), 114.3 (CH2), 81.9
(CH), 78.5 (CH), 74.8 (CH2), 74.0 (CH2), 72.2 (CH), 71.2 (CH), 64.3 (CH2), 34.6 (CH2),
34.1 (CH2), 30.0 (CH2), 29.9 (2 ꢁ CH2, coincident), 29.8 (CH2), 29.7 (CH2), 29.5 (CH2),
29.3 (CH2), 26.2 (3 ꢁ CH3, coincident), 18.6 (C), ꢀ4.8 (CH3), ꢀ4.9 (CH3); IR nmax
3442, 2926, 1640, 1455, 1252, 1090, 836, 778, 698 cmꢀ1; HRMS Calcd for C36H58O5Si:
[M + Na]+ m/z 621.3951. Found 621.3938.

Asymmetric Total Synthesis of Broussonetine C
725
(2R,3R,4R,5S)-3,4-Bis(phenylmethyloxy)hexadec-15-ene-1,2,5-triol (6). A solu-
tion of compound 5 (15 g, 25.08 mmol) in 2M methanolic HCl (100 mL) was stirred at
0°C under an atmosphere of nitrogen. After 3 h, the reaction mixture was concentrated
under reduced pressure to afford a yellow oil. Flash chromatography (0%–15% v/v
ethyl acetate-hexane elution) gave 6 (10.5 g, 86%) as a clear colourless oil: [a]D + 7
1
(c 1.3, CHCl3); H NMR (300 MHz) d 7.38–7.25 (m, 10H), 5.80 (m, 1H), 5.03ꢀ4.90
(complex m, 2H), 4.70 (d, J = 11.3 Hz, 1H), 4.60 (d, J = 4.1 Hz, 2H), 4.51 (d, J = 11.3
Hz, 1H), 3.90 (m, 1H), 3.80 (m, 1H), 3.74 (dd, J = 4.6 and 2.5 Hz, 2H), 3.46 (m, 2H),
2.04 (app q. J = 6.7 Hz, 2H), 1.50ꢀ1.20 (m, 18H); 13C NMR (75 MHz) d 139.3 (CH),
138.0 (C), 137.6 (C), 128.7 (CH), 128.6 (2 ꢁ CH, coincident), 128.5 (CH), 128.4
(2 ꢁ CH, coincident), 128.3 (CH), 128.2 (2 ꢁ CH, coincident), 128.1 (CH), 114.3
(CH2), 80.9 (CH), 77.6 (CH), 74.3 (CH2), 73.9 (CH2), 72.3 (CH), 70.3 (CH), 68.8 (CH2),
35.0 (CH2), 34.1 (CH2), 30.0 (CH2), 29.9 (2 ꢁ CH2, coincident), 29.8 (CH2), 29.5 (CH2),
29.3 (2 ꢁ CH2, coincident); IR nmax 3405, 2923, 2247, 1640, 1455, 1065, 909, 734, 698
cmꢀ1; HRMS Calcd for C30H44O5: [M + Na]+ m/z 507.3086. Found 507.3076.
(4R)-4-[1R,2R,3S-1,2-Bis(phenylmethyloxy)-3-hydroxy-13-tetradecen-1-yl]-2-
phenyl-1,3-dioxolane (7). Benzaldehyde dimethyl acetal (BDMA) (1.67 mL, 11.15
mmol) was added dropwise to a solution of compound 6 (4.5 g, 9.30 mmol) and p-
TsOH (catalytic) in CH2Cl2 (90 mL) maintained at –20°C under a nitrogen atmo-
sphere. The reaction mixture was allowed to warm to 10°C over 1 h, then treated with
1M aq NaOH (90 mL). The separated aq layer was extracted with CH2Cl2 (3 ꢁ 100
mL), and the combined organic phases were washed with brine (1 ꢁ 250 mL) before
being dried (MgSO4), filtered and concentrated under reduced pressure to afford a pale
yellow oil. Flash chromatography (0%–20% v/v ethyl acetate-hexane elution) gave 7
1
(3.7 g, 70%) as a clear colourless oil: [a]D + 9 (c 1.0, CHCl3); H NMR (300 MHz) d
7.38ꢀ7.25 (m, 15H), 5.80 (m, 1H), 5.70 (s, 1H), 5.08ꢀ4.96 (complex m, 2H), 4.82
(d, J = 11.5 Hz, 1H), 4.80 (d, J = 11.2 Hz, 1H), 4.75 (d, J = 11.4 Hz, 1H), 4.60
(d, J = 11.3 Hz, 1H), 4.30 (dd, J = 8.2 and 2.4 Hz, 1H), 4.14 (t, J = 7.8 Hz, 1H), 4.03
(t, J = 4.4 Hz, 1H), 3.78 (br m, 1H), 3.47 (dd, J = 3.3 and 1.1 Hz, 1H), 2.23 (br s, 1H),
2.09 (app q, J = 6.9 Hz, 2H), 1.55ꢀ1.30 (m, 18H); 13C NMR (75 MHz) d 139.4 (CH),
138.4 (C), 138.1 (C), 137.4 (C), 129.5 (CH), 129.3 (CH), 128.6 (CH), 128.5 (CH),
128.3 (CH), 128.2 (2 ꢁ CH, coincident), 128.1 (CH), 128.0 (CH), 127.9 (2 ꢁ CH,
coincident), 126.9 (CH), 126.8 (CH), 126.6 (CH), 126.5 (CH), 114.4 (CH2), 103.7
(CH), 81.4 (CH), 78.8 (CH), 77.5 (CH), 74.7 (CH2), 71.0 (CH), 67.1 (CH2), 34.9
(CH2), 34.2 (CH2), 30.0 (2 ꢁ CH2, coincident), 29.9 (2 ꢁ CH2, coincident), 29.5
(CH2), 29.3 (CH2, coincident); IR nmax 3483, 2925, 2247, 1639, 1455, 1091, 910, 732,
697 cmꢀ1; HRMS Calcd for C37H48O5: [M + Na]+ m/z 595.3399. Found 595.3399.
(4R)-4-[1R,2R,3S-1,2-Bis(phenylmethyloxy)-3-azido-13-tetradecen-1-yl]-2-phe-
nyl-1,3-dioxolane (9). Et3N (1.87 mL, 13.45 mmol) was added, dropwise, to a stirred
solution of compound 7 (3.5 g, 6.11 mmol) in CH2Cl2 (60 mL), maintained at 0°C
under an atmosphere of nitrogen. After 10 min, MsCl (1.05 mL, 13.45 mmol) was
added dropwise over 5 min. The reaction mixture thus obtained was allowed to warm
to room temperature over 1.5 h, then treated with saturated aq NH4Cl (60 mL). The
separated aq layer was extracted with CH2Cl2 (3 ꢁ 50 mL) and the combined organic
phases were washed with brine (1 ꢁ 200 mL) before being dried (MgSO4), filtered and
concentrated under reduced pressure to afford (4R)-4-[1R,2R,3S-1,2-bis-(phenylmethy-

726
Perlmutter and Vounatsos
loxy)-3-methanesulfonyloxy-13-tetradecen-1-yl]-2-phenyl-1,3-dioxolane (8) as a pale
yellow oil (3.7 g). Sodium azide (1.25 g, 19.37 mmol) was added, in portions, to a
solution of the crude mesylate 8 (3.7 g) in DMF (20 mL) and heated to 60°C under an
atmosphere of nitrogen. After 18 h, the reaction mixture was treated with saturated aq
NH4Cl (50 mL) and CH2Cl2 (100 mL). The separated aq layer was extracted with
CH2Cl2 (3 ꢁ 80 mL), and the combined organic phases were washed with water
(3 ꢁ 350 mL), and brine (1 ꢁ 350 mL), before being dried (MgSO4), filtered and
concentrated under reduced pressure to afford a yellow oil. Flash chromatography
(0%–15% v/v ethyl acetate-hexane elution) gave 9 (2.8 g, 80%) as a clear yellow oil:
1
[a]D + 8 (c 0.8, CHCl3); H NMR (300 MHz) d 7.38ꢀ7.25 (m, 15H), 5.80 (m, 1H),
5.02ꢀ4.90 (complex m, 2H), 4.56 (d, J = 1.7 Hz, 2H), 4.53 (s, 1H), 4.50 (d, J = 1.9
Hz, 2H), 4.20 (m, 1H), 4.00 (t, J = 3.4 Hz, 1H), 3.95 (m, 1H), 3.79 (dd, J = 2.8 and 1.8
Hz, 1H), 3.56 (m, 2H), 2.03 (app q, J = 6.9 Hz, 2H), 1.40ꢀ1.20 (m, 18H); 13C NMR
(75 MHz) d 139.4 (CH), 138.3 (C), 138.1 (C), 137.2 (C), 129.5 (CH), 129.4 (CH),
128.7 (CH), 128.5 (CH), 128.3 (2 ꢁ CH, coincident), 128.2 (CH), 128.1 (2 ꢁ CH,
coincident), 128.0 (CH), 127.9 (CH), 126.9 (CH), 126.8 (2 ꢁ CH, coincident), 126.6
(CH), 114.3 (CH2), 103.7 (CH), 88.2 (CH), 85.7 (CH), 82.7 (CH), 81.4 (CH), 73.6
(CH2), 72.0 (CH2), 70.5 (CH2), 34.1 (CH2), 33.7 (CH2), 29.8 (CH2), 29.5 (2 ꢁ CH2,
coincident), 29.3 (2 ꢁ CH2, coincident), 29.2 (2 ꢁ CH2, coincident); IR nmax 2925,
2099, 1731, 1496, 1364, 1098, 909, 734, 897 cmꢀ1; HRMS Calcd for C37H47N3O4:
[M + Na]+ m/z 620.3464. Found 620.3456.
(2R,3R,4R,5R)-1,3,4-Tris(phenylmethyloxy)-5-azidohexadec-15-en-2-ol (10).
AlCl3 (2.1 g, 15.8 mmol) was added, in portions, to a solution of compound 9 (2.7
g, 4.51 mmol) and BH3.NMe3 (1.15 g, 15.8 mmol) in THF (45 mL) maintained at 0°C
under an atmosphere of nitrogen. After 3 h, the reaction mixture was treated with water
(50 mL) and extracted with diethyl ether (3 ꢁ 60 mL). The combined organic extracts
were washed with saturated aq NaHCO3 (150 mL) and brine (1 ꢁ 150 mL) before
being dried (MgSO4), filtered and concentrated under reduced pressure to afford a
yellow oil. Flash chromatography (0%–15% v/v ethyl acetate-hexane elution) gave 10
(2.4 g, 89%) as a yellow oil: [a]D + 17 (c 1.5, CHCl3); 1H NMR (300 MHz) d
7.30ꢀ7.22 (m, 15H), 5.80 (m, 1H), 5.03ꢀ4.92 (complex m, 2H), 4.73 (d, J = 11.2 Hz,
1H), 4.66 (d, J = 11.2 Hz, 1H), 4.64 (d, J = 11.3 Hz, 1H), 4.55 (d, J = 11.1 Hz, 1H),
4.53 (s, 2H), 3.97 (m, 1H), 3.74 (d, J = 6.5 Hz, 2H), 3.67 (complex m, 2H), 3.54 (m,
1H), 2.56 (d, J = 5.9 Hz, 1H), 2.05 (app q, J = 6.7 Hz, 2H), 1.40ꢀ1.27 (m, 18H); 13C
NMR (75 MHz) d 139.3 (CH), 138.2 (C), 138.1 (C), 138.0 (C), 128.8 (CH), 128.7
(2 ꢁ CH, coincident), 128.6 (CH), 128.5 (2 ꢁ CH, coincident), 128.3 (CH), 128.2
(2 ꢁ CH, coincident), 128.1 (CH), 127.8 (2 ꢁ CH, coincident), 126.9 (CH), 126.8
(2 ꢁ CH, coincident), 114.3 (CH2), 81.0 (CH), 79.2 (CH), 74.8 (CH2), 74.5 (CH2), 73.7
(CH2), 71.2 (CH2), 70.3 (CH), 62.8 (CH), 34.1 (CH2), 32.2 (CH2), 30.5 (2 ꢁ CH2,
coincident), 30.0 (CH2), 29.8 (2 ꢁ CH2, coincident), 29.4 (CH2), 29.3 (CH2); IR nmax
3465, 2923, 2100, 1640, 1454, 1069, 909, 733, 697 cmꢀ1; HRMS Calcd for
C37H49N3O4: [M + Na]+ m/z 622.3620. Found 622.3609.
(2S,3R,4R,5R)-1,3,4-Tris(phenylmethyloxy)-2-p-nitrobenzoyloxy-5-azidohexa-
dec-15-enyl (11). DEAD (1.78 mL, 11.3 mmol) was added dropwise at rt to a
solution of compound 10 (2.4 g, 5.7 mmol) containing PPh3 (2.9 g, 11.3 mmol) and

Asymmetric Total Synthesis of Broussonetine C
727
p-nitrobenzoic acid (1.9 g, 11.3 mmol) in THF (57 mL) under a nitrogen atmosphere.
After 18 h at rt, the reaction mixture was diluted with water (80 mL), and the resulting
solution was extracted with diethyl ether (3 ꢁ 100 mL). The combined organic extracts
were washed with saturated aq NaHCO3 (250 mL) and brine (1 ꢁ 250 mL) before
being dried (MgSO4), filtered and concentrated under reduced pressure to afford a
yellow oil. Flash chromatography (0%–20% v/v ethyl acetate-hexane elution) gave 11
1
(2.6 g, 88%) as a pale yellow oil: [a]D + 10 (c 1.0, CHCl3); H NMR (300 MHz) d
8.26 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.30ꢀ7.22 (m, 15H), 5.80 (m, 1H),
5.00 (q, J = 5.1 and 4.8 Hz, 1H), 5.02ꢀ4.91 (complex m, 2H), 4.78 (d, J = 11.4 Hz,
1H), 4.68 (d, J = 11.3 Hz, 1H), 4.63 (d, J = 11.3 Hz, 1H), 4.60 (d, J = 11.4 Hz, 1H),
4.58 (d, J = 12.1 Hz, 1H), 4.41 (d, J = 12.2 Hz, 1H), 4.06 (t, J = 5.2 Hz, 1H),
3.70ꢀ3.60 (complex m, 3H), 3.53 (m, 1H), 2.04 (app q, J = 6.7 Hz, 2H), 1.37ꢀ1.26
(m, 18H); 13C NMR (75 MHz) d 139.4 (CH), 138.0 (C), 137.8 (C), 137.0 (C), 135.4
(C), 131.0 (2 ꢁ CH, coincident), 128.7 (2 ꢁ CH, coincident), 128.6 (2 ꢁ CH,
coincident), 128.5 (2 ꢁ CH, coincident), 128.3 (CH), 128.0 (2 ꢁ CH, coincident),
127.9 (2 ꢁ CH, coincident), 127.5 (2 ꢁ CH, coincident), 127.3 (2 ꢁ CH, coincident),
123.7 (2 ꢁ CH, coincident), 114.3 (CH2), 80.8 (CH), 78.1 (CH), 75.4 (CH2), 74.3
(CH), 74.1 (CH2), 73.5 (CH2), 68.2 (CH2), 63.0 (CH), 34.1 (2 ꢁ CH2, coincident), 30.0
(CH2), 29.9 (2 ꢁ CH2, coincident), 29.8 (2 ꢁ CH2, coincident), 29.5 (CH2), 29.2
(CH2); IR nmax 2923, 2100, 1728, 1530, 1270, 910, 783, 696 cmꢀ1; HRMS Calcd for
C44H52N4O7: [M + Na]+ m/z 771.3733. Found 771.3742.
(2S,3R,4R,5R)-1,3,4-Tris(phenylmethyloxy)-2-p-nitrobenzoyloxy-5-aminohexa-
dec-15-enyl (12). PPh3 (3.4 g, 13.0 mmol) was added to a solution of compound 11
(2.6 g, 4.3 mmol) in THF:H2O (4.5 mL of a 10:1 v/v mixture), and heated to reflux (ca.
60°C). After 4 h, the reaction mixture was cooled to rt and partitioned between diethyl
ether (20 mL) and saturated aq NH4Cl (30 mL). The separated aqueous layer was
extracted with diethyl ether (3 ꢁ 25 mL) and washed with brine (1 ꢁ 80 mL) before
being dried (MgSO4), filtered and concentrated under reduced pressure to afford a
yellow oil. Flash chromatography (0%–25% v/v ethyl acetate-hexane elution) gave 12
1
(2.12 g, 85%) as a pale yellow oil: [a]D + 9 (c 3.3, CHCl3); H NMR (300 MHz) d
7.33ꢀ7.25 (m, 15H), 5.82 (m, 1H), 5.04ꢀ4.92 (complex m, 2H), 4.06 (m, 1H), 3.80
(m, 1H), 3.67ꢀ3.60 (complex m, 2H), 3.51 (m, 1H), 3.22 (broad s, 1H), 3.09 (m, 1H),
2.05 (app q, J = 6.8 Hz, 2H), 1.50ꢀ1.24 (m, 18H); 13C NMR (75 MHz) d 139.4 (CH),
138.6 (C), 138.4 (C), 138.3 (C), 128.7 (2 ꢁ CH, coincident), 128.6 (2 ꢁ CH,
coincident), 128.5 (3 ꢁ CH, coincident), 128.4 (CH), 128.3 (2 ꢁ CH, coincident),
128.0 (2 ꢁ CH, coincident), 127.9 (2 ꢁ CH, coincident), 127.7 (CH), 114.3 (CH), 80.8
(CH), 78.5 (CH), 74.1 (CH2), 73.3 (CH2), 73.0 (CH2), 71.3 (CH2), 67.4 (CH), 53.3
(CH), 34.1 (CH2), 33.5 (CH2), 30.0 (2 ꢁ CH2, coincident), 29.9 (2 ꢁ CH2, coincident),
29.5 (CH2), 29.3 (CH2); IR nmax 3372, 2924, 2854, 1730, 1640, 1454, 1070, 909,
807, 733 cmꢀ1; HRMS Calcd for C37H51NO4: [M + Na]+ m/z 596.3715. Found
596.3712.
(2S,3R,4R,5R)-1,3,4-Tris(phenylmethyloxy)-5-aminohexadec-15-en-2-ol (13).
Sodium hydroxide (2.26 g, 56.5 mmol) was added to a solution of 12 (4.24 g, 5.6
mmol) in MeOH (56 mL) at 0°C. After 1 h, the reaction mixture was warmed to rt and
partitioned between diethyl ether (200 mL) and 5% aq HCl (100 mL). The separated aq

728
Perlmutter and Vounatsos
layer was extracted with diethyl ether (3 ꢁ 150 mL) and washed with brine (1 ꢁ 250
mL) before being dried (MgSO4), filtered and concentrated under reduced pressure to
afford an orange oil. Flash chromatography (0%–30% v/v ethyl acetate-hexane elution)
1
gave 13 (2.6 g, 76%) as a clear colourless oil: [a]D + 21 (c 1.5, CHCl3); H NMR (300
MHz) d 7.30ꢀ7.22 (m, 15H), 5.80 (m, 1H), 5.04ꢀ4.92 (complex m, 2H), 4.78 (d,
J = 11.3 Hz, 1H), 4.70 (s, 2H), 4.53 (d, J = 11.2 Hz, 1H), 4.50 (d, J = 11.3 Hz, 1H),
4.44 (d, J = 11.3 Hz, 1H), 3.90ꢀ3.73 (complex m, 3H), 3.49 (m, 3H), 2.50 (d, J = 7.1
Hz, 1H), 2.05 (app q, J = 6.8 Hz, 2H), 1.50ꢀ127 (m, 18H); 13C NMR (75 MHz) d
139.3 (CH), 138.2 (C), 138.1 (C), 138.0 (C), 128.6 (2 ꢁ CH, coincident), 128.5
(2 ꢁ CH, coincident), 128.3 (2 ꢁ CH, coincident), 128.0 (2 ꢁ CH, coincident), 127.9
(CH), 127.8 (CH), 127.5 (CH), 126.8 (2 ꢁ CH, coincident), 126.5 (CH), 126.4 (CH),
114.3 (CH2), 81.8 (CH), 78.6 (CH), 75.2 (CH2), 74.7 (CH2), 73.6 (CH2), 71.4 (CH2),
70.1 (CH), 63.6 (CH), 34.1 (2 ꢁ CH2, coincident), 30.0 (2 ꢁ CH2, coincident), 29.8
(CH2), 29.7 (CH2), 29.4 (2 ꢁ CH2, coincident), 29.3 (CH2); IR nmax 3450, 2925, 2101,
1731, 1640, 1454, 1111, 909, 755, 697 cmꢀ1; HRMS Calcd for C37H49N3O4:
[M + Na]+ m/z 622.3620. Found 622.3620.
(2S,3R,4R,5R)-1,3,4-Tris(phenylmethyloxy)-5-{[(1,1-dimethylethoxy)carbonyl]
amino}-hexadec-15-en-2-ol (14). Et3N (0.56 mL, 4.0 mmol) was added, dropwise, to a
solution of compound 13 (1.92 g, 3.3 mmol) in THF (33 mL), maintained at 0°C under a
nitrogen atmosphere. After 10 min, (Boc)2O (876 mg, 4.0 mmol) was added, and the
reaction mixture was allowed to warm to rt over 2 h before being treated with saturated aq
NH4Cl (25 mL) and water (25 mL). The separated aq layer was extracted with diethyl
ether (3 ꢁ 50 mL) and washed with brine (1 ꢁ 100 mL) before being dried (MgSO4),
filtered and concentrated under reduced pressure to afford a pale yellow oil. Flash
chromatography (0%–30% v/v ethyl acetate-hexane elution) gave 14 (1.8 g, 80%) as a
1
clear colourless oil: [a]D + 26 (c 0.75, CHCl3); H NMR (300 MHz) d 7.33ꢀ7.25 (m,
15H), 5.81 (m, 1H), 5.03ꢀ4.90 (complex m, 2H), 4.73 (d, J = 11.2 Hz, 1H), 4.67 (d,
J = 11.2 Hz, 1H), 4.63 (d, J = 11.5 Hz, 1H), 4.58 (d, J = 11.5 Hz, 1H), 4.47 (s, 2H), 4.03
(m, 1H), 3.89 (m, 1H), 3.75ꢀ3.66 (complex m, 2H), 3.49 (d, J = 6 Hz, 2H), 2.92 (d,
J = 5.3 Hz, 1H), 2.04 (app q, J = 6.8 Hz, 2H), 1.4 (s, 9H), 1.35ꢀ1.26 (m, 18H); 13C NMR
(75 MHz) d 139.4 (CH), 138.4 (C), 138.3 (2 ꢁ C), 128.6 (3 ꢁ CH, coincident), 128.5
(3 ꢁ CH, coincident), 128.3 (3 ꢁ CH, coincident), 128.0 (3 ꢁ CH, coincident), 127.9
(3 ꢁ CH, coincident), 114.3 (CH2), 80.8 (CH), 79.3 (CH), 74.8 (CH2), 73.6 (CH2), 71.3
(CH2), 70.9 (CH), 50.9 (CH), 34.1 (2 ꢁ CH2, coincident), 29.9 (2 ꢁ CH2, coincident),
29.8 (2 ꢁ CH2, coincident), 29.5 (2 ꢁ CH2, coincident), 29.3 (CH2), 28.7 (3 ꢁ CH3,
coincident); IR nmax 3429, 3064, 3061, 2925, 2855, 1713, 1497, 1454, 1365, 1173, 909,
733, 697 cmꢀ1; HRMS Calcd for C42H59NO6: [M + Na]+ m/z 696.4239. Found 696.4227.
(2R,3R,4R,5R)-N-{[(1,1-Dimethylethoxy)carbonyl]amino}-2-[(phenylmethoxy)-
methyl]-3,4-bis-(phenylmethyloxy)-5-(undec-1-en-11-yl)pyrrolidine (16). Et3N (0.8
mL, 5.7 mmol) was added, dropwise, to a stirred solution of compound 14 (1.75 g, 2.6
mmol) in CH2Cl2 (26 mL), maintained at 0°C under an atmosphere of nitrogen. After
10 min, MsCl (0.44 mL, 5.7 mmol) was added, dropwise, over 5 min. The reaction
mixture thus obtained was allowed to warm to rt 1.5 h, then treated with saturated aq
NH4Cl (30 mL). The separated aqueous layer was extracted with CH2Cl2 (3 ꢁ 40 mL)
and the combined organic phases were washed with brine (1 ꢁ 120 mL) before being
dried (MgSO4), filtered and concentrated under reduced pressure to afford (2S,3R,4R,

Asymmetric Total Synthesis of Broussonetine C
729
5R)-1,3,4-tris-(phenylmethyloxy)-2-methanesulfonyloxy-5-{[(1,1-dimethylethoxy)carbo-
nyl]amino}-hexadec-15-enyl (15) as a pale yellow oil (1.95 g). Potassium tert-butoxide
(7.8 mL of 1M solution in THF, 7.8 mmol) was added dropwise to a solution of crude
15 (1.95 g) in CH2Cl2 (26 mL) maintained at 0°C under an atmosphere of nitrogen.
After 18 h at rt, the reaction mixture was treated with saturated aq NH4Cl (30 mL). The
separated aqueous layer was extracted with CH2Cl2 (3 ꢁ 40 mL), and the combined
organic phases were washed with brine (1 ꢁ 120 mL) before being dried (MgSO4),
filtered and concentrated under reduced pressure to afford a pale yellow oil. Flash
chromatography (0%–15% v/v ethyl acetate-hexane elution) gave 16 (1.6 g, 93%) as a
1
clear colourless oil: [a]Dꢀ30 (c 0.85, CHCl3); H NMR (300 MHz) d 7.30ꢀ7.22 (m,
15H), 5.80 (m, 1H), 5.04ꢀ4.92 (complex m, 2H), 4.64 (m, 2H), 4.44 (complex m, 5H),
4.15 (d, J = 6.2 Hz, 1H), 4.02 (m, 1H), 3.76 (m, 2H), 3.51 (d, J = 9.0 Hz, 1H), 3.44 (d,
J = 9.0 Hz, 1H), 2.04 (app q, J = 6.7 Hz, 2H), 1.43 (d, J = 14.5 Hz, 9H), 1.37ꢀ1.26 (m,
18H); 13C NMR (75 MHz) d 139.4 (CH), 138.4 (C), 138.2 (2 ꢁ C), 128.6 (3 ꢁ CH,
coincident), 128.5 (3 ꢁ CH, coincident), 128.4 (3 ꢁ CH, coincident), 127.8 (3 ꢁ CH,
coincident), 127.7 (3 ꢁ CH, coincident), 114.3 (CH2), 84.8 (CH), 83.6 (CH), 73.2 (CH2),
71.0 (CH2), 69.0 (CH2), 64.9 (CH), 62.7 (CH), 34.1 (CH2), 32.3 (CH2), 31.8 (CH2), 30.6
(CH2), 30.0 (CH2), 29.9 (CH2), 29.8 (CH2), 29.7 (CH2), 29.5 (CH2), 28.8 (3 ꢁ CH3,
coincident); IR 3063, 2927, 1682, 1496, 1455, 1265, 1174, 1097, 912, 738, 699 nmax
cmꢀ1; HRMS Calcd for C42H57NO5: [M + Na]+ m/z 678.4134. Found 678.4129.
(2R,3R,4R,5R)-N-{[(1,1-dimethylethoxy)carbonyl]amino}-2-[(phenylmethoxy)-
methyl]-3,4-bis-(phenylmethyloxy)-5-(1-oxodecan-11-yl)-pyrrolidine (18).
K2OsO4.2H2O (112 mg, 3.0 mmol) was added, in one portion, to a solution of com-
pound 16 (1.6 g, 2.4 mmol) in acetone:H2O (24 mL of a 1:1 v/v mixture), maintained at
0°C. After 10 min, N-methylmorpholine oxide (1.4 g, 4.9 mmol) was added, dropwise, to
the reaction mixture. After 3 h at rt, the reaction mixture was diluted with water (30 mL)
and the resulting solution was extracted with ethyl acetate (3 ꢁ 40 mL). The combined
organic phases were washed with brine (120 mL) before being dried (MgSO4), filtered
and concentrated under reduced pressure to afford (2R,3R,4R,5R)-N-{[(1,1-dimethy-
lethoxy)carbonyl]amino}-2-[(phenylmethoxy)methyl]-3,4-bis-(phenylmethyloxy)-5-(1,2-
dihydroxyundecan-11-yl)-pyrrolidine (17) as a pale yellow oil (1.5 g). Sodium periodate
(745 mg, 3.5 mmol) was added in one portion to a solution of crude 17 (800 mg, 1.2
mmol) in diethyl ether:H2O (10 mL of a 1:1 v/v mixture), maintained at 0°C. After 2 h at
room temperature the reaction mixture was diluted with water (20 mL) and the resulting
solution was extracted with diethyl ether (3 ꢁ 30 mL). The combined organic phases
were washed with brine (1 ꢁ 100 mL) before being dried (MgSO4), filtered and
concentrated under reduced pressure to afford 18 as a pale yellow oil. Flash
chromatography (0%–15% v/v ethyl acetate-hexane elution) gave 18 (740 mg, 88%)
1
as a clear colourless oil: [a]Dꢀ30 (c 2.7, CHCl3); H NMR (300 MHz) d 9.75 (s, 1H),
7.31ꢀ7.23 (m, 15H), 4.62 (m, 2H), 4.51ꢀ4.34 (complex m, 5H), 4.15 (d, J = 6.2 Hz,
1H), 4.02 (m, 1H), 3.80ꢀ3.72 (m, 2H), 3.46 (m, 1H), 2.41 (app t, J = 7.4 Hz, 2H), 1.43
(d, J = 14.5 Hz, 9H), 1.37ꢀ1.18 (m, 18H); 13C NMR (75 MHz) d 202.2 (CO), ester,
138.4 (C), 138.1 (C), 138.0 (C), 129.9 (3 ꢁ CH, coincident), 129.1 (3 ꢁ CH,
coincident), 128.5 (3 ꢁ CH, coincident), 128.4 (3 ꢁ CH, coincident), 127.8 (3 ꢁ CH,
coincident), 84.8 (CH), 83.6 (CH), 73.2 (CH2), 71.4 (CH2), 71.0 (CH2), 68.2 (CH2), 64.9
(CH), 62.6 (CH), 44.2 (CH2), 34.0 (CH2), 31.7 (CH2), 30.6 (CH2), 29.9 (CH2), 29.8
(2 ꢁ CH2, coincident), 29.7 (2 ꢁ CH2, coincident), 28.8 (3 ꢁ CH3, coincident); IR

730
Perlmutter and Vounatsos
3014, 2930, 1722, 1684, 1454, 1395, 1217, 1097, 758 nmax cmꢀ1; HRMS Calcd for
C41H55NO6: [M + Na]+ m/z 680.3926. Found 680.3899.
(2R,3R,4R,5R)-N-{[(1,1-dimethylethoxy)carbonyl]amino}2-[(phenylmethoxy)-
methyl]-3,4-bis-(phenylmethyloxy)-5-(1-phenylmethyloxy-4-hydroxytridecan-13-
yl)pyrrolidine (19). Benzyloxypropylmagnesium bromide (1.5 mL of a 1 M solution in
THF, 1.5 mmol) was added dropwise to neat aldehyde 18 (760 mg, 1.15 mmol) main-
tained at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at rt for 3 h,
then treated with saturated aq NH4Cl (10 mL). The mixture thus obtained was partitioned
between diethyl ether (3 ꢁ 15 mL) and the combined organic phases were washed with
brine (1 ꢁ 40 mL) before being dried (MgSO4), filtered and concentrated under reduced
pressure to afford a pale yellow oil. Flash chromatography (0%ꢀ15% v/v ethyl acetate-
hexane elution) gave 19 (650 mg, 70%) as a clear colourless oil: [a]D –18.4 (c 0.5,
1
CHCl3); H NMR (300 MHz) d 7.33ꢀ7.25 (m, 20H), 4.62 (m, 2H), 4.53 (d, J = 2.9 Hz,
2H), 4.51ꢀ4.34 (complex m, 5H), 4.15 (d, J = 6.2 Hz, 1H), 4.02 (m, 1H), 3.82ꢀ3.75 (m,
2H), 3.67 (t, J = 5.7 Hz, 2H), 3.53ꢀ3.44 (m, 2H), 3.32ꢀ2.2 (m, 4H), 1.88 (quintet, J = 5.6
Hz, 2H), 1.43 (d, J = 14.5 Hz, 9H), 1.7ꢀ1.2 (m, 18H); 13C NMR (75 MHz) d 154.2 (CO),
138.8 (C), 138.5 (C), 138.2 (C), 137.9 (C), 128.6 (3 ꢁ CH, coincident), 128.5 (3 ꢁ CH,
coincident), 128.4 (3 ꢁ CH, coincident), 127.9 (3 ꢁ CH, coincident), 127.8 (3 ꢁ CH,
coincident), 127.7 (3 ꢁ CH, coincident), 127.6 (2 ꢁ CH, coincident), 84.9 (CH), 83.5
(CH), 73.2 (CH2), 71.4 (CH2), 71.9 (CH), 71.1 (CH2), 70.8 (CH2), 69.0 (CH2), 64.9 (CH),
62.8 (CH), 62.3 (CH2), 37.9 (CH2), 35.1 (CH2), 32.4 (CH2), 32.3 (CH2), 31.8 (CH2), 30.6
(2 ꢁ CH2, coincident), 30.0 (2 ꢁ CH2, coincident), 29.8 (CH2), 29.7 (2 ꢁ CH2, co-
incident), 28.8 (3 ꢁ CH3, coincident); IR nmax 3463, 3018, 2928, 1683, 1454, 1394, 1173,
1096, 928, 751, 688 cmꢀ1; HRMS Calcd for C51H69NO7: [M + Na]+ m/z 830.4971. Found
830.4945.
(2R,3R,4R,5R)-N-{[(1,1-dimethylethoxy)carbonyl]amino}2-[(phenylmethoxy)-
methyl]-3,4-bis-(phenylmethyloxy)-5-[1-phenylmethyloxy-4-oxy-tridecan-13-yl]pyr-
rolidine (20). Dess-Martin Periodinane (787 mg, 1.85 mmol) was added, in portions, to
a solution of compound 19 (500 mg, 0.62 mmol) in CH2Cl2 (2 mL) maintained at 0°C
under a nitrogen atmosphere. After 3 h, the reaction mixture was diluted with CH2Cl2 (10
mL) then treated with 1M aq Na2S2O3 (5 mL) and 1M aq NaHCO3 (5 mL). After being
stirred vigorously for 15 min, the reaction mixture was extracted with CH2Cl2 (3 ꢁ 10
mL) and the combined organic phases were washed with brine (1 ꢁ 20 mL) before being
dried (MgSO4), filtered and concentrated under reduced pressure to afford a pale yellow
oil. Flash chromatography (0%–15% v/v ethyl acetate-hexane elution) gave 20 (450 mg,
90%) as a clear colourless oil: [a]D + 12 (c 0.5, CHCl3); 1H NMR (300 MHz) d
7.33ꢀ7.25 (m, 20H), 4.62 (m, 2H), 4.53ꢀ4.34 (complex m, 7H), 4.15 (d, J = 6.2 Hz,
1H), 4.02 (m, 1H), 3.83ꢀ3.78 (m, 2H), 3.47 (m, 1H), 2.71 (t, J = 7.2 Hz, 2H), 2.51 (t,
J = 7.2 Hz, 2H), 1.88 (quintet, J = 7.2 Hz, 2H), 1.45 (d, J = 14.5 Hz, 9H), 1.37ꢀ1.18 (m,
18H); 13C NMR (75 MHz) d 210.8 (C), 154.2 (CO), 138.8 (C), 138.5 (C), 138.2 (C),
137.9 (C), 128.6 (3 ꢁ CH, coincident), 128.5 (3 ꢁ CH, coincident), 128.4 (3 ꢁ CH,
coincident), 127.9 (3 ꢁ CH, coincident), 127.8 (3 ꢁ CH, coincident), 127.7 (3 ꢁ CH,
coincident), 127.6 (2 ꢁ CH, coincident), 84.9 (CH), 83.5 (CH), 73.2 (CH2), 71.4 (CH2),
71.9 (CH), 71.1 (CH2), 70.8 (CH2), 69.0 (CH2), 64.9 (CH), 62.8 (CH), 62.3 (CH2), 42.9
(CH2), 35.7 (2 ꢁ CH2, coincident), 32.4 (CH2), 32.3 (CH2), 31.8 (CH2), 30.6 (2 ꢁ CH2,
coincident), 30.0 (2 ꢁ CH2, coincident), 29.8 (CH2), 29.7 (2 ꢁ CH2, coincident), 28.8

Asymmetric Total Synthesis of Broussonetine C
731
(3 ꢁ CH3, coincident); IR nmax 3018, 2920, 1715, 1693, 1496, 1454, 1392, 1109, 737,
697 cmꢀ1; HRMS Calcd for C51H67NO7: [M + Na]+ m/z 828.4815. Found 828.4808.
N-Boc Broussonetine C (21). Palladium black (10 mg) was added in one portion
to a solution of compound 20 (50 mg, 0.06 mmol) in EtOH (0.6 mL) containing 3%
acetic acid. The reaction mixture was stirred for 18 h at rt under an atmosphere of
hydrogen. The reaction mixture was then filtered through a bed of CeliteTM, and the
solvent was concentrated under reduced pressure to afford 21 (20 mg, 70%) as an
amorphous white solid: [a]D + 15 (c 0.1, CHCl3); 1H NMR (300 MHz) d 4.72
(t, J = 6.4 Hz, 1H), 4.44 (t, J = 6.4 Hz, 1H), 4.28 (dd, J = 11.0 and 5.0 Hz, 1H), 4.22
(dd, J = 11.0 and 5.0 Hz, 1H), 3.92 (t, J = 7.3 Hz, 2H), 3.85 (m, 1H), 3.56 (m, 1H),
2.71 (t, J = 7.3 Hz, 2H), 2.44 (t, J = 7.3 Hz, 2H), 2.12 (quintet, J = 7.3 Hz, 2H), 2.04
(m, 2H), 1.62ꢀ1.15 (m, 16H), 1.45 (d, J = 14.5 Hz, 9H); 13C NMR (75 MHz) d 210.8
(C), 154.2 (CO), 84.4 (CH), 80.4 (CH), 65.3 (CH), 62.9 (CH), 61.4 (2 ꢁ CH2,
coincident), 42.9 (CH2), 35.7 (2 ꢁ CH2, coincident), 30.2 (CH2), 29.9 (CH2), 29.7
(2 ꢁ CH2, coincident), 29.5 (CH2), 28.8 (3 ꢁ CH3, coincident), 27.9 (CH2), 27.3
(CH2), 24.2 (CH2); IR nmax 3405, 2920, 1704, 1693, 1496, 1454, 1352, 1098, cmꢀ1
HRMS Calcd for C23H43NO7: [M + Na]+ m/z 468.2937. Found 468.2925.
;
Broussonetine C (1). Trifluroacetic acid (0.2 mL) was added, dropwise, to a
solution of 21 (15 mg, 0.04 mmol) in CH2Cl2 (0.5 mL) maintained at 0°C under a
nitrogen atmosphere. The reaction mixture was stirred for 2 h after which time the
solution was subsequently concentrated under reduced pressure. The residue was then
stirred with diethyl ether (3 mL) whereupon the product crystallized. The solid material
was collected by filtration, and washed with ether (3 ꢁ 2 mL) to afford Broussonetine
C (8 mg, 60%): mp 146–149°C (lit.[2] mp 147–149°C); [a]D + 32 (c 0.40, MeOH)
1
{lit.[2] [a]D + 25 (c 0.96, MeOH)}; H NMR (300 MHz) d 4.72 (t, J = 6.4 Hz, 1H),
4.44 (t, J = 6.4 Hz, 1H), 4.28 (dd, J = 11.0 and 5.0 Hz, 1H), 4.22 (dd, J = 11.0 and 5.0
Hz, 1H), 3.92 (t, J = 7.3 Hz, 2H), 3.85 (m, 1H), 3.56 (m, 1H), 2.71 (t, J = 7.3 Hz, 2H),
2.44 (t, J = 7.3 Hz, 2H), 2.12 (q, J = 7.3 Hz, 2H), 2.04 (m, 1H), 1.75 (m, 1H), 1.62 (m,
2H), 1.62ꢀ1.15 (m, 14H); 13C NMR (75 MHz) d 210.8 (CO), 84.4 (CH), 80.4 (CH),
65.3 (CH), 62.9 (CH), 61.41 (2 ꢁ CH2, coincident), 42.9 (CH2), 35.7 (2 ꢁ CH2,
coincident), 30.2 (CH2), 29.9 (CH2), 29.8 (2 ꢁ CH2, coincident), 29.5 (CH2), 27.9
(CH2), 27.3 (CH2), 24.2 (CH2).
ACKNOWLEDGMENT
F.V. is grateful to the Australian Government for support through an Australian
Postgraduate Award.
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Received February 28, 2003
Accepted July 23, 2003