Total Synthesis of Calystegine B4

Article abstract of DOI:10.1002/ejoc.201000157

The total synthesis of calystegine B₄ was achieved in 10 steps from (-)-D-lyxose by using a new synthetic strategy to obtain the requisite protected hydroxylated 4-aminocyclohept-2-en1-one without the problem of regioisomer formation that was a problem in the earlier synthesis of this natural product. The key steps included a Petasis-borono-Mannich reaction and a ring-closing metathesis reaction.

Full text of DOI:10.1002/ejoc.201000157

FULL PAPER
DOI: 10.1002/ejoc.201000157
Total Synthesis of Calystegine B4
Panawan Moosophon,[a,b] Morwenna C. Baird,[a] Somdej Kanokmedhakul,[b] and
Stephen G. Pyne*[a]
Keywords: Mannich reaction / Metathesis / Natural products / Total synthesis
The total synthesis of calystegine B4 was achieved in 10 steps
from (–)- -lyxose by using a new synthetic strategy to obtain
the requisite protected hydroxylated 4-aminocyclohept-2-en-
1-one without the problem of regioisomer formation that was
a problem in the earlier synthesis of this natural product. The
key steps included a Petasis–borono-Mannich reaction and a
ring-closing metathesis reaction.
D
Introduction
The calystegine alkaloids comprise 13 different poly-
hydroxylated, 1-hydroxynortropane molecules and one tri-
hydroxylated 1-aminonortropane (calystegine N1).[1,2] In
addition, the N-methyl derivatives of calystegine B2 and C1
are also natural products along with the glycoside deriva-
tives.[1,2] This group, along with the polyhydroxylated pyr-
rolidine, piperidine, indolizidine and pyrrolizidine alkaloids,
have glycosidase inhibitory activities and thus have poten-
tial utility as antiviral, anticancer, antidiabetic and anti-
obesity drugs.[3] These potentially useful biological activities
along with the novel hemiaminal structure of the calysteg-
ine alkaloids have made these compounds and their ana-
logues attractive and important synthetic targets.[4–10] A sig-
nificant number of these syntheses have employed a ring-
closing metathesis (RCM) reaction of a protected di- or
trihydroxylated 4-amino-1,8-octadiene 1 to provide a pro-
tected di- or tri-hydroxylated 4-aminocycloheptene
2.[5a,6,7,8a,8b] Hydroboration of the alkene functionality of 2,
followed by oxidation of the resulting secondary alcohol
then provided a protected hydroxylated 4-aminocyclohept-
anone 3, which upon deprotection underwent hemiaminal
formation to provide the 1-hydroxynorptropane structure 4
of the target natural product or analogue. One major prob-
lem with this synthetic strategy is that the hydroboration
reaction occurs with moderate regioselectivity (typically
3:1), in favour of the desired secondary alcohol, giving ulti-
mately mixtures of the ketones 3 and 4 (Scheme 1). Separa-
tion of these ketones and then global deprotection of the
major regioisomer 3 then gives the target nortropane 5
(Scheme 1).
Scheme 1. Previous RCM/hydroboration/oxidation strategy for ca-
lystegine synthesis.
One way of avoiding this regioselectivity problem is to
employ the RCM reaction on a protected polyhydroxylated
3-oxo- or 3-hydroxy-7-amino-1,8-octadiene 6a or 6b. Start-
ing from 6a for example, the requisite protected hydroxyl-
ated 4-aminocycloheptenone 7a would be obtained directly
without the possibility of regioisomeric ketones (Scheme 2).
Alternatively, ketone 7a could be accessed by oxidation of
the ring-closed product 7b. In this paper we report the syn-
thesis of calystegine B4 (20) using this new synthetic strat-
egy.
Calystegine B4 (20) was first isolated in 1996 from the
root extracts of Scopolia japonica.[1c] Of the glycosidases
screened against this molecule, the strongest inhibitory ac-
tivity found was against pig kidney trehalase, with an
IC50 of 4.8 µ.[1c] To date the only total synthesis of
[a] School of Chemistry, University of Wollongong,
Wollongong NSW 2522, Australia
E-mail: spyne@uow.edu.au
[b] Department of Chemistry, University of Khon Kaen,
Khon Kaen 40002, Thailand
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000157.
Eur. J. Org. Chem. 2010, 3337–3344
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. Moosophon, M. C. Baird, S. Kanokmedhakul, S. G. Pyne
FULL PAPER
Scheme 2. New strategy for calystegine synthesis.
calystegine B4 (20) is that of Madsen,[7] who used the RCM/
hydroboration/oxidation strategy shown in Scheme 1 to pre-
pare not only 20 but also calystegines B2 and B3.
Results and Discussion
The synthesis of calystegine B4 (20) is outlined in
Scheme 3. The Petasis–borono-Mannich reaction of (–)--
lyxose (8) with benzylamine and [(E)-2-phenylvinyl]boronic
acid gave the aminotetrol 9 in 82% yield (Scheme 3).[11]
This compound was treated with (Boc)2O under basic con-
ditions (Et3N, MeOH) to efficiently provide the N-Boc-pro-
tected product 10 in 89% yield. The primary alcohol of 10
underwent regioselective O-tritylation to give 11 before the
remaining alcohol groups were protected as O-benzyl ethers
to give 12. The O-trityl group of 12 was selectively removed
to give 13, which was easily oxidised to the aldehyde 14.
Treatment of this aldehyde with vinylmagnesium bromide
Scheme 3. Reagents and conditions: (a) (E)-PhCH=CHB(OH)2,
BnNH2, EtOH, room temp., 3 d; (b) (Boc)2O, Et3N, MeOH, room
temp., 3 d; (c) TrCl, pyridine, room temp., 1 d; (d) BnBr, Ag2O,
Bu4NI, room temp., 16 h; (e) pTsOH, CHCl3, MeOH, room temp.,
16 h; (f) Dess–Martin periodinane, CH2Cl2, room temp. (for 14,
1.5 h; for 18, 30 min; for 19, 30 min); (g) CH2=CHMgBr, THF,
0 °C to room temp., 3 h; (h) Grubbs’ 2nd generation catalyst,
CH2Cl2, microwave irradiation at 90 °C (for 17, 1.5 h; for 19, 2 h);
(i) 20% Pd(OH)2/C, H2, THF/H2O (1:1), room temp., 4.5 h; then
PdCl2, H2, THF/H2O (1:1), room temp., 4 h; then PdCl2, H2,
MeOH, room temp., 1.5 h; and then Amberlyst® A-26(OH) as
resin.
1
gave a 1:1 mixture of the alcohols 15/16 from H NMR
analysis of the crude reaction mixture. This poor diastereo-
selectivity, however, was not of a major concern since this
carbinol centre was to be oxidized to the corresponding
ketone in future steps. However, we decided to separate
these diastereomers by column chromatography to examine
their independent chemistry. In this way the carbinols 15
and 16 were obtained diastereomerically pure in 29% and
23% overall yields from 13, respectively.
The RCM reaction of 15 by using Grubbs’ 2nd genera-
tion ruthenium catalyst with microwave heating at 90 °C for
90 min gave the desired cycloheptenol 17 in 77% yield after the 6-H signal was a doublet (9.5 Hz). This information and
purification. The RCM reaction of the diastereomer 16, the observed NOESY correlations between 1-H and 4-H
however, was much slower under similar conditions. After and 4-H and 6-H (Scheme 4) confirmed the equatorial con-
three successive treatments of 16 with Grubbs’ 2nd genera- figuration of the hydroxy group of 22. Consistent with this
1
tion catalyst with microwave heating at 90 °C for 2 h, the assignment were the vicinal couplings observed in the H
yield of the cycloheptene 22 was in contrast only 37% NMR spectrum of 15 for 5-H and 6-H. The former proton
(Scheme 4). To assist in the identification of the stereo- resonated as a doublet of doublets with one 1,2-diaxial-like
chemistry of 17 and 22 these individual products were coupling (J4,5 = 7.5 Hz) and one 1,2-axial-equatorial-like
treated with acid to remove their N-Boc groups, which pro- coupling (J5,6 = 2.5 Hz), whereas the 6-H signal was a
vided compounds 21 and 23, respectively, which showed doublet (J4,5 = 7.5 Hz) (Scheme 4). This is in agreement
1
sharp NMR signals (Scheme 4). The H NMR spectrum of with an axial-like configuration of the 4-OH group in 21.
22 showed that 5-H had two 1,2-diaxial vicinal couplings Further supporting evidence for these stereochemical as-
and resonated as an apparent triplet of ca. 9 Hz, whereas signments came from the reduction of 19 with NaBH4/
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Total Synthesis of Calystegine B4
CeCl3·7H2O, which gave exclusively the equatorial alcohol oxidation to the enone 18 first, and then an RCM reaction
22 (Scheme 5); this reducing reagent is known to favour the of 18 gave 19 in 57% yield (Scheme 3). This RCM reaction
formation of the equatorial alcohol product in the re- was much faster and more efficient than that of its alcohol
ductions of cyclic ketones and enones.[12]
congener 16.
After many unsuccessful attempts to convert enone 19 to
calystegine B4 (20), we found the best method to achieve
this was by first treatment of 19 with Pd(OH)2/H2 in THF/
H2O to reduce the double bond and remove one or two
benzyl groups (as evident from ESIMS analysis). The crude
reaction mixture was then treated with PdCl2/H2 in THF/
H2O to removed more benzyl groups, and finally treatment
with PdCl2/H2 in MeOH removed the remaining benzyl
groups and the Boc group due to in situ formation of
HCl.[11d] The hydrochloride salt of 20 was deprotonated
and purified by ion exchange chromatography using Am-
berlyst® A-26(OH) resin to give 20 in 51% overall yield and
in 92–95% purity according to 1H NMR analysis. Attempts
to purify this material further were not successful. It is
worth noting that 20 gives a much clearer and more re-
1
solved H NMR spectrum when run in [D5]pyridine/D2O
1
(4:1) than just D2O. The H NMR spectrum of 20 in [D5]-
pyridine/D2O (4:1) was essentially identical to that of the
natural product run in the same solvent.[1c] The 13C NMR
chemical shifts in D2O, however, were all 2.2 ppm upfield
from those reported for the natural product. These types of
consistent differences in the 13C NMR spectroscopic data
have been noted before for azasugars.[11d,11f] The signal of
the quaternary carbon atom C-1 of 20 was not observed
but was able to be confirmed by gHMBC correlations. The
optical rotation of the synthetic product [α]1D9 = –29.5 (c =
0.185, H2O) was of the same sign but different in magnitude
to that of the natural product [α]D = –63.0 (c = 0.65, H2O)
or to that prepared earlier by synthesis {[α]D = –46.4 (c =
0.18, H2O)}.[7] In our case the lower optical rotation may
be a reflection of the 92–95% purity of our compound.
Scheme 4. Reagents and conditions: (a) MeOH, HCl, room temp.,
18 h.
Conclusions
We have developed a 10-step synthesis of calystegine B4
(20) using the Petasis–borono-Mannich reaction to intro-
duce the amino group with the correct configuration. This
synthesis produced two diene carbinol diastereomers (15
and 16) that underwent the RCM reaction at different rates
and efficiencies. One diene carbinol diastereomer (15)
Scheme 5. Reagents and conditions: (a) CeCl3·7H2O, NaBH4,
MeOH, room temp., 20 min.
We speculate that the difference in rates in the RCM re- efficiently gave the key fully functionalized 4-aminocyclo-
actions of 15 and 16 is due to coordination of the secondary hept-2-en-1-one 19 after an RCM reaction and then oxi-
hydroxy group to the Ru centre in intermediates A and B dation. Deprotection then gave the natural product target.
(Scheme 4). In intermediate B such coordination would The other diene carbinol diastereomer (16) efficiently gave
make it energetically more difficult for the ruthenium– the same key cyclohept-2-en-1-one 19 after first oxidation
carbene double bond to be parallel to the styrene double and then an RCM reaction. In this way both diastereomeric
bond that is required for the RCM process resulting in a diene carbinols could be efficiently processed through to the
much reduced rate of reaction.
natural product target 20. The overall yield of 20 via the
Oxidation of 17 by using the Dess–Martin periodinane diene carbinol 15 was 4.7%, whereas that from diene carbi-
then gave the enone 19 (Scheme 3). Whereas the same nol 16 was 3.4%. This synthetic method should be useful
ketone could be obtained from the oxidation of 22, the for the preparation of other calystegines and their epimers
most efficient way to prepare enone 19 from 16 involved its and analogues by using different sugar starting materials.
Eur. J. Org. Chem. 2010, 3337–3344
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3339

P. Moosophon, M. C. Baird, S. Kanokmedhakul, S. G. Pyne
FULL PAPER
product was purified by column chromatography [EtOAc/petro-
leum ether (20:80 to 30:70)] to give 11 as a white solid in 81% yield
(8.596 g, 12.55 mmol). Rf = 0.19 [EtOAc/petroleum ether (20:80)];
m.p. 62–68 °C (clear), 120–125 °C (melted). LRMS (ESI): m/z (%)
= 683.7 (68) [M – H]+. HRMS (ESI): m/z = 708.3315 [M + Na]+,
Experimental Section
General: General methods were as described previously.[11d]
(2R,3R,4R,5R,E)-5-(Benzylamino)-7-phenylhept-6-ene-1,2,3,4-tetra-
ol (9): To a solution of (–)--lyxose (200 mg, 1.332 mmol) in etha-
nol (2 mL) was added benzylamine (0.146 mL, 142.7 mg,
1.332 mmol) and [(E)-2-phenylvinyl]boronic acid (197.1 mg,
1.332 mmol), and the mixture was stirred at room temp. for 3 d.
The reaction was monitored by ESIMS. The solvent was removed
in vacuo and the crude product purified by column chromatog-
raphy (EtOAc to 20% MeOH/EtOAc) to give 9 as a brown foamy
solid in 82% yield (375.7 mg, 1.095 mmol). A small amount was
repurified for analysis to give a white solid. Rf = 0.22 [EtOAc/
MeOH/NH3 (8:1:1)]; m.p. 114–116 °C. LRMS (ESI): m/z (%) =
343.8 (100) [M + H]+. HRMS (ESI): m/z = 344.1867 [M + H]+,
calcd. for C H NO Na 708.3301. IR: ν = 3396, 3063, 2976,
˜
max
44 47
6
1660, 1450, 1368, 1161, 1076 cm–1. [α]2D3 = +9.40 (c = 1.18, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.37 (d, J = 7.5 Hz, 6 H, 6ϫ
ArCH), 7.32–7.19 (m, 19 H, 19ϫ ArCH), 6.54 (dd, J = 15.5,
8.5 Hz, 1 H, 2-H), 6.29 (d, J = 16.0 Hz, 1 H, 1-H), 5.87 (br. s, 1 H,
OH), 4.55 (d, J = 15.5 Hz, 1 H, 1ϫ NCH2), 4.33 (d, J = 14.0 Hz, 1
H, 1ϫ NCH2), 4.18 (br. s, 2 H, 1ϫ CHOH and 3-H), 3.85 (d, J =
9.0 Hz, 1 H, 1ϫ CHOH), 3.29 (m, 3 H, 2ϫ 7-H and 1ϫ CHOH),
2.86 (d, J = 6.0 Hz, 1 H, OH), 2.57 (d, J = 8.5 Hz, 1 H, OH), 1.47
(s, 9 H, 9ϫ CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 157.3
(C=O), 143.5 (ArC), 138.0 (ArC), 136.7 (ArC), 133.9 (C-1), 128.5
(ArCH), 128.4 (ArCH), 127.9 (ArCH), 127.8 (ArCH), 127.7
(ArCH), 127.4 (ArCH), 127.1 (ArCH), 126.6 (ArCH), 122.6 (C-2),
87.2 (C-Ph3), 81.3 [C-(CH3)3], 75.8 (CHOH), 71.6 (CHOH), 68.6
(CHOH), 66.1 (C-7), 64.5 (C-3), 53.6 (NCH2), 28.4 (CH3) ppm.
calcd. for C H NO 344.1862. IR: νmax = 3355, 3283, 2909, 2848,
˜
20 26
4
2356, 1491, 1347, 1019 cm–1. [α]2D4 = –45.8 (c = 0.95, CH3OH). H
NMR (500 MHz, CD3OD): δ = 7.45 (d, J = 8 Hz, 2 H, 2ϫ ArCH),
7.32 (m, 6 H, 6ϫ ArCH), 7.23 (m, 2 H, 2ϫ ArCH), 6.58 (d, J =
16.0 Hz, 1 H, 7-H), 6.22 (dd, J = 16.0, 9.0 Hz, 1 H, 6-H), 3.88 (d,
J = 13.0 Hz, 1 H, 1ϫ NCH2), 3.87 (d, J = 7.0 Hz, 1 H, 2-H), 3.80
(ddd, J = 9.0, 5.0, 2 Hz, 1 H, 3-H or 4-H), 3.69 (d, J = 13.0 Hz, 1
H, 1ϫ NCH2), 3.60 (d, J = 6.5 Hz, 2 H, 2ϫ 1-H), 3.53 (apparent
br. d, J = 9.0 Hz, 2 H, 3-H or 4-H and 5-H) ppm. 13C NMR
(125 MHz, CD3OD): δ = 140.6 (ArC), 138.4 (ArC), 135.6 (C-7),
129.7 (ArCH), 129.6 (ArCH), 129.5 (ArCH), 128.6 (ArCH), 128.4
(ArCH), 128.2 (C-6), 127.5 (ArCH), 74.1 (C-3 or C-4), 72.8 (C-3
or C-4), 71.8 (C-2), 64.8 (C-1), 64.3 (C-5), 51.6 (NCH2) ppm.
1
tert-Butyl
(1E,3R,4R,5R,6R)-N-Benzyl-4,5,6-tris(benzyloxy)-1-
phenyl-7-(trityloxy)hept-1-en-3-ylcarbamate (12): To a solution of
11 (979.2 mg, 1.429 mmol) in benzyl bromide (3.6 mL) was added
tetrabutylammonium iodide (57.0 mg, 0.154 mmol), and the mix-
ture was stirred at room temp. for 25 min before adding silver oxide
(3.216 g, 13.88 mmol). The reaction mixture was stirred at room
temp. overnight and was then filtered through Celite and the sol-
vent removed in vacuo. Triethylamine was added to the residue and
the mixture stirred for 45 min, then diluted with H2O. The product
was extracted with diethyl ether (3ϫ20 mL) and dried (MgSO4).
The crude product was purified by column chromatography
[EtOAc/petroleum ether (0:100 to 5:95)] to give 12 as an off-white
semicrystalline solid in 57% yield (771.8 mg, 0.808 mmol). Rf =
0.44 [EtOAc/petroleum ether (20:80)]. LRMS (ESI): m/z (%) =
955.3 (6) [M + H]+. HRMS (ESI): m/z = 973.4932 [M + H]+, calcd.
tert-Butyl
(1E,3R,4R,5R,6R)-N-Benzyl-4,5,6,7-tetrahydroxy-1-
phenylhept-1-en-3-ylcarbamate (10): To a solution of 9 (373.5 mg,
1.089 mmol) in methanol (3.3 mL) was added triethylamine
(0.3 mL, 220.4 mg, 2.178 mmol), then di-tert-butyl dicarbonate
(594.1 mg, 2.722 mmol). The reaction mixture was stirred at room
temp. for 1 d. The volatiles were removed in vacuo, and the residue
was purified by column chromatography [EtOAc/petroleum ether
(80:20) to EtOAc to MeOH/EtOAc (15:85)] to give 10 as a white
solid in 89% yield (431.3 mg, 0.974 mmol) (73% over 2 steps). (–)-
-Lyxose can be taken through to 10 in one pot, but gives a lower
yield (62% over 2 steps). Rf = 0.26 [EtOAc/petroleum ether
(20:80)]; m.p. 144–146 °C. LRMS (ESI) = m/z (%) = 443.8 (100)
[M + H]+. HRMS (ESI): m/z = 444.2379 [M + H]+, calcd. for
for C H NO 973.4918. IR: νmax = 3048, 2899, 2346, 1690, 1450,
˜
65 67
7
1158, 1067 cm–1. [α]2D5 = –21.9 (c = 1.2, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.45 (m, 6 H, 6ϫ ArCH), 7.37 (d, J =
7.5 Hz, 3 H, 3ϫ ArCH), 7.30–7.28 (m, 8 H, 8ϫ ArCH), 7.24–7.16
(m, 14 H, 14ϫ ArCH), 7.14–7.12 (m, 3 H, 3ϫ ArCH), 7.09 (br. s,
3 H, 3ϫ ArCH), 7.00 (br. s, 3 H, 3ϫ ArCH), 6.42 (br. m, 1 H, 1-
H), 6.32 (br. m, 1 H, 2-H), 4.74 (d, J = 11.5 Hz, 1 H, 1ϫ OCH2Ph-
5 or -6), 4.73 (s, 2 H, OCH2Ph-5 or -6), 4.66 (d, J = 12.0 Hz, 1 H,
1ϫ OCH2Ph-5 or -6), 4.58 (d, J = 11.5 Hz, 1 H, 1ϫ OCH2Ph-4),
4.47 (m, 1 H, 3-H), 1.37 (d, J = 11.5 Hz, 1 H, 1ϫ OCH2Ph-4),
4.20 (br. s, 1 H, 5-H), 4.11 (m, 1 H, 4-H), 3.57 (br. s, 1 H, 6-H),
3.53 (dd, J = 10.0, 3.0 Hz, 1 H, 1ϫ 7-H), 3.28 (br. s, 1 H, 1ϫ 7-
H), 1.25 (s, 9 H, 9ϫ CH3) ppm; NCH2 signal not observed due to
peak broadening. 13C NMR (125 MHz, CDCl3): δ = 155.5 (C=O),
144.0 (ArC), 139.3 (ArC), 138.8 (ArC), 138.6 (ArC), 137.3 (ArC),
133.5 (C-1), 128.7 (ArCH), 128.2 (ArCH), 128.1 (ArCH), 128.0
(ArCH), 127.8 (ArCH), 127.5 (ArCH), 127.4 (ArCH), 127.3
(ArCH), 127.2 (ArCH), 127.1 (ArCH), 127.0 (ArCH), 126.6
(ArCH), 126.3 (C-2), 86.7 (C-Ph3), 80.6 (C-4), 79.9 (C-5), 79.1 (C-
6), 74.5 (OCH2Ph-5 or -6), 73.1 (OCH2Ph-4), 73.0 (OCH2Ph-5 or -
6), 63.6 (C-7), 60.6 (C-3), 59.7 (rotamer C-3), 50.9 (NCH2), 28.4
(CH3) ppm.
C25H34NO6 444.2386. IR: ν
= 3442, 3314, 2976, 1614, 1416,
˜
max
1158, 1078, 1040 cm–1. [α]2D4 = –80.5 (c = 1.12, CH3OH). H NMR
(500 MHz, CD3OD): δ = 7.21 (m, 8 H, 8ϫ ArCH), 7.13 (d, J =
4.0 Hz, 2 H, 2ϫ ArCH), 6.43 (br. s, 2 H, 2-H and 1-H), 4.80 (s, 1
H, 3-H), 4.63 (br. s, 2 H, 2ϫ NCH2), 4.00 (d, J = 9.0 Hz, 1 H, 4-
H), 3.87 (t, J = 6.5 Hz, 1 H, 6-H), 3.59 (d, J = 6.5 Hz, 2 H, 7-H),
1
3.34 (d, J = 9.0 Hz, 1 H, 5-H), 1.35 (br. s, 9 H, 9ϫ CH3) ppm. 13
C
NMR (125 MHz, CD3OD): δ = 158.1 (C=O), 141.0 (ArC), 138.3
(ArC), 136.0 (C-1), 129.5 (ArCH), 129.4 (ArCH), 129.2 (ArCH),
129.16 (ArCH), 128.7 (ArCH), 128.2 (ArCH), 128.06 (ArCH),
127.7 (ArCH), 127.5 (ArCH), 127.4 (ArCH), 124.3 (C-2), 81.8 [C-
(CH3)3], 75.6 (C-4), 71.9 (C-5), 71.3 (C-6), 64.8 (C-7), 62.7 (C-3),
52.0 (NCH2), 28.6 (CH3) ppm.
tert-Butyl (1E,3R,4R,5R,6R)-N-Benzyl-4,5,6-trihydroxy-1-phenyl-7-
(trityloxy)hept-1-en-3-ylcarbamate (11): To
a solution of 10
(6.862 g, 15.49 mmol) in dry pyridine (47.0 mL) was added trityl
chloride (6.477 g, 23.23 mmol), and the mixture was stirred under
N2 at room temp. for 1 d. The reaction was quenched with H2O
and the mixture extracted with CH2Cl2 (3ϫ70 mL). The combined
organic extracts were washed with saturated CuSO4 solution
(2ϫ70 mL), then brine (2ϫ70 mL) and dried (MgSO4). The crude
tert-Butyl (1E,3R,4R,5R,6R)-N-Benzyl-4,5,6-tris(benzyloxy)-7-hy-
droxy-1-phenylhept-1-en-3-ylcarbamate (13): To a solution of 12
(599.2 mg, 0.627 mmol) in chloroform (1.6 mL) and methanol
(16 mL) was added p-toluenesulfonic acid (11.9 mg, 0.063 mmol)
in methanol (8 mL), and the reaction mixture was stirred at room
temp. overnight. The reaction was quenched with saturated
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Total Synthesis of Calystegine B4
NaHCO3 (2 mL) and mixture extracted with CH2Cl2 (3ϫ20 mL).
The combined organic extracts were washed with brine (50 mL)
and dried (MgSO4). The crude product was purified by column
chromatography [EtOAc/petroleum ether (10:90 to 20:80)] to give
13 as a colourless oil in 85% yield (379.3 mg, 0.532 mmol). Rf =
0.33 [EtOAc/petroleum ether (30:70)]. LRMS (ESI): m/z (%) =
713.4 (35) [M + H]+, 730.6 (35) [M + NH3]+. HRMS (ESI): m/z =
(m, 5 H, 4ϫ OCH2Ph and 3-H), 4.46 (d, J = 11.5 Hz, 1 H, 1ϫ
OCH2Ph), 4.35 (d, J = 5.5 Hz, 1 H, 7-H), 4.25 (br. s, 3 H, NCH2
and CHOBn), 3.91 (br. s, 1 H, CHOBn), 3.71 (t, J = 5.5 Hz, 1 H,
CHOBn), 2.68 (br. s, 1 H, OH), 1.42 (s, 9 H, 9ϫ CH3) ppm. 13C
NMR (125 MHz, CDCl3): δ = 155.6 (C=O), 139.1 (ArC), 138.5
(ArC), 138.3 (ArC), 137.3 (C-8), 137.1 (ArC), 133.9 (C-1), 128.35
(ArCH), 128.29 (ArCH), 128.26 (ArCH), 128.1 (ArCH), 128.0
(ArCH), 127.9 (ArCH), 127.8 (ArCH), 127.60 (ArCH), 127.55
(ArCH), 127.3 (ArCH), 126.8 (C-2), 126.4 (ArCH), 117.0 (C-9),
714.3810 [M + H]+, calcd. for C46H52NO6 714.3795. IR: ν
=
˜
max
3442, 3027, 2935, 1687, 1450, 1163, 1058 cm–1. [α]2D0 = –22.9 (c =
1.7, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.39–7.28 (m, 10 81.6 (CHOBn), 80.6 (CHOBn), 80.4 (CHOBn), 74.4 (OCH2Ph),
H, 10ϫ ArCH), 7.24–7.21 (m, 6 H, 6ϫ ArCH), 7.17 (m, 5 H, 5ϫ 74.3 (OCH2Ph), 73.1 (OCH2Ph), 72.9 (C-7), 60.3 (C-3), 50.6
ArCH), 7.07 (m, 4 H, 4ϫ ArCH), 6.47 (br. m, 1 H, 1-H or 2-H), (NCH2), 28.4 (CH3) ppm.
6.08 (br. m, 1 H, 1-H or 2-H), 4.77 (d, J = 11.5 Hz, 1 H, 1ϫ
16: Rf = 0.36 [EtOAc/petroleum ether (20:80)]. LRMS (ESI): m/z
(%) = 740.7 (43) [M + H]+. HRMS (ESI): m/z = 740.3967 [M +
H]+, calcd. for C H NO 740.3951. IR: ν
= 3476, 3032, 2919,
OCH2Ph), 4.76 (s, 2 H, 2ϫ OCH2Ph), 4.70 (d, J = 5.0 Hz, 1 H,
1ϫ OCH2Ph), 4.67 (d, J = 4.5 Hz, 1 H, 1ϫ OCH2Ph), 4.51 (d, J
= 12.0 Hz, 1 H, 1ϫ OCH2Ph), 4.37 (br. s, 1 H, 3-H), 4.20 (d, J =
15.5 Hz, 2 H, NCH2), 3.99 (d, J = 7.0 Hz, 1 H, CHOBn), 3.84–
3.82 (m, 1 H, 1ϫ 7-H), 3.75 (br. s, 1 H, 1ϫ 7-H), 3.67 (quint, J =
3.5 Hz, 1 H, CHOBn), 1.36 (s, 9 H, 9ϫ CH3) ppm; signal of 1ϫ
CHOBn not seen due to peak broadening. 13C NMR (125 MHz,
CDCl3): δ = 155.4 (C=O), 143.5 (ArC), 138.9 (ArC), 138.7 (ArC),
138.4 (ArC), 137.2 (ArC), 133.5 (poss. C-1), 128.7 (ArCH), 128.5
(ArCH), 128.4 (ArCH), 128.30 (ArCH), 128.26 (ArCH), 128.13
(ArCH), 128.08 (ArCH), 128.0 (ArCH), 127.9 (ArCH), 127.83
(ArCH), 127.75 (ArCH), 127.7 (ArCH), 127.6 (ArCH), 127.2 (poss.
C-2), 126.9 (ArCH), 126.4 (ArCH), 80.3 (CHOBn), 79.9 (CHOBn),
79.3 (CHOBn), 74.6 (OCH2Ph), 73.0 (OCH2Ph), 72.8 (OCH2Ph),
61.5 (C-7), 61.2 (C-3), 51.4 (NCH2), 28.4 (CH3) ppm.
˜
max
48 54
6
1685, 1450, 1162, 1063 cm–1. [α]2D4 = –34.3 (c = 0.53, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.30–7.02 (m, 25 H, 25ϫ ArCH),
6.52 (br. s, 1 H, 1-H or 2-H), 6.16 (br. s, 1 H, 1-H or 2-H), 5.97 (t,
J = 11.5 Hz, 1 H, 8-H), 5.40 (d, J = 17.0 Hz, 1 H, 1ϫ 9-H), 5.21
(d, J = 8.5 Hz, 1 H, 1ϫ 9-H), 4.86 (d, J = 9.5 Hz, 1 H, 1ϫ
OCH2Ph), 4.78 (m, 2 H, 2ϫ OCH2Ph), 4.71 (d, J = 11.0 Hz, 1 H,
1ϫ OCH2Ph), 4.62 (dd, J = 11.0, 2.0 Hz, 1 H, 1ϫ OCH2Ph), 4.57
(m, 1 H, 3-H), 4.49 (m, 1 H, 1ϫ OCH2Ph), 4.40 (m, 1 H, 7-H),
4.27 (d, J = 13.0 Hz, 2 H, 2ϫ NCH2), 4.06 (s, 1 H, CHOBn), 3.68
(br. s, 1 H, CHOBn), 2.84 (br. s, 1 H, OH), 1.36 (s, 9 H, 9ϫ CH3)
ppm; signal of 1ϫ CHOBn not seen due to peak broadening. 13C
NMR (125 MHz, CDCl3): δ = 155.7 (C=O), 138.8 (C-8), 137.2
(ArC), 134.9 (ArC), 133.6 (poss. C-1), 128.3 (ArCH), 128.2
(ArCH), 128.0 (ArCH), 127.7 (ArCH), 127.5 (ArCH), 127.1
(ArCH), 126.4 (ArCH), 115.3 (C-9), 82.0 (CHOBn), 81.0
(CHOBn), 75.2 (OCH2Ph), 74.6 (OCH2Ph), 73.0 (OCH2Ph), 71.8
(C-7), 60.7 (C-3), 51.1 (NCH2), 28.4 (CH3) ppm; several signals
were not seen due to extensive peak broadening.
tert-Butyl (1E,3R,4R,5R,6S)-N-Benzyl-4,5,6-tris(benzyloxy)-7-oxo-
1-phenylhept-1-en-3-ylcarbamate (14), tert-Butyl (1E,3R,4R,5R,
6R,7R)-N-Benzyl-4,5,6-tris(benzyloxy)-7-hydroxy-1-phenylnona-
1,8-dien-3-ylcarbamate (15) and tert-Butyl N-Benzyl-(1E,3R,4R,
5R,6R,7S)-4,5,6-tris(benzyloxy)-7-hydroxy-1-phenylnona-1,8-dien-
3-ylcarbamate (16): To a solution of 13 (1.005 g, 1.410 mmol) in dry
CH2Cl2 (47.2 mL) was added Dess–Martin periodinane (897.1 mg,
2.115 mmol), and the mixture was stirred at room temp. under N2
for 1.5 h. The mixture was then diluted with diethyl ether (18 mL)
and the reaction quenched with saturated NaHCO3 solution
(18 mL) and sodium thiosulfate (5.5 g). The product was extracted
with diethyl ether (3ϫ60 mL), and the combined organic extracts
were washed with saturated NaHCO3 solution (100 mL), then H2O
(100 mL) and dried (MgSO4). The solvent was removed to give the
crude aldehyde 14 as a yellow oil in 91% yield (916.5 mg,
tert-Butyl (1R,2Z,4R,5R,6R,7R)-N-Benzyl-5,6,7-tris(benzyloxy)-4-
hydroxycyclohept-2-enylcarbamate (17): To
a solution of 15
(22.2 mg, 0.030 mmol) in anhydrous CH2Cl2 (1.47 mL) was added
10 mol-% Grubbs’ 2nd generation catalyst (2.55 mg, 0.003 mmol).
The mixture was subjected to microwave irradiation in a sealed
tube in a CEM Discover microwave reactor at 90 °C, 100 W and
100 psi for 2 h. The solvent was then removed and the product
purified by column chromatography [EtOAc/petroleum ether (5:95
to 15:85)] to give 11 as a colourless oil in 77% yield (14.7 mg,
0.023 mmol). Rf = 0.20 [EtOAc/petroleum ether (20:80)]. LRMS
(ESI): m/z (%) = 636 (100) [M + H]+. HRMS (ESI): m/z = 636.3339
1.289 mmol). Then, to
a solution of crude 14 (916.5 mg,
1.289 mmol) in dry THF (18.1 mL) was added vinylmagnesium
bromide (1.0  THF, 1.93 mL, 1.934 mmol) at 0 °C under N2. The
mixture was then warmed to room temp. and stirred for 2 h before
quenching the reaction with saturated ammonium chloride solution
(12 mL); CH2Cl2 (12 mL) was added, and the product was ex-
tracted with CH2Cl2 (3ϫ50 mL) and dried (MgSO4). The crude
products were purified and separated by column chromatography
[EtOAc/petroleum ether (5:95 to 10:90)] to give 15 as a colourless
oil in 29.4% yield (306.0 mg, 0.414 mmol) and 16 as a colourless
oil in 23.4% (243.8 mg, 0.330 mmol).
[M + H]+, calcd. for C H NO 636.3325. IR: ν
= 3432, 2960,
˜
max
40 46
6
2919, 1685, 1455, 1261, 1062 cm–1. [α]2D3 = –55.2 (c = 1.47, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.36–7.24 (m, 16 H, 16ϫ ArCH),
7.17 (t, J = 7.0 Hz, 2 H, 2ϫ ArCH), 7.12 (m, 2 H, 2ϫ ArCH),
5.70 (d, J = 12.0 Hz, 1 H, 2-H or 3-H), 5.33 (d, J = 11.0 Hz, 1 H,
2-H or 3-H), 5.03 (br. s, 2 H, 1-H and 4β-H), 4.93 (d, J = 11.5 Hz,
1 H, 1ϫ OCH2Ph), 4.84 (d, J = 11.5 Hz, 1 H, 1ϫ OCH2Ph), 4.74
(d, J = 11.5 Hz, 1 H, 1ϫ OCH2Ph-6), 4.63 (m, 1 H, 1ϫ OCH2Ph),
4.61 (t, J = 4.0 Hz, 1 H, 1ϫ OCH2Ph), 4.57 (d, J = 11.5 Hz, 1 H,
1ϫ OCH2Ph-6), 4.50 (br. s, 1 H, 5-H or 7-H), 4.49 (d, J = 13.0 Hz,
1 H, 1ϫ NCH2), 4.25 (br. s, 1 H, 1ϫ NCH2), 4.06 (t, J = 4.5 Hz,
1 H, 5-H or 7-H), 3.74 (d, J = 6.0 Hz, 1 H, 6-H), 2.78 (d, J =
9.5 Hz, 1 H, OH), 1.31 (s, 9 H, 9ϫ CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 155.7 (C=O), 140.7 (ArC), 138.2 (ArC),
15: Rf = 0.29 [EtOAc/petroleum ether (20:80)]. LRMS (ESI): m/z
(%) = 740.7 (41) [M + H]+. HRMS (ESI): m/z = 740.3972 [M +
H]+, calcd. for C H NO 740.3951. IR: ν
= 3032, 2920, 1690,
˜
max
48 54
6
1450, 1368, 1162, 1067 cm–1. [α]2D4 = –7.13 (c = 0.44, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.35–7.23 (m, 11 H, 11ϫ ArCH),
7.24–7.17 (m, 11 H, 11ϫ ArCH), 7.11 (m, 3 H, 3ϫ ArCH), 6.45 136.1 (C-2 or C-3), 128.5 (ArCH), 128.4 (ArCH), 128.3 (ArCH),
(br. s, 1 H, 2-H), 6.18 (br. s, 1 H, 1-H), 6.02 (ddd, J = 6.5 Hz, 1 H, 128.0 (ArCH), 127.9 (ArCH), 127.75 (ArCH), 127.67 (ArCH),
8-H), 5.37 (d, J = 17.5 Hz, 1 H, 1ϫ 9-H), 5.25 (d, J = 10.0 Hz, 1 126.6 (ArCH), 126.2 (ArCH), 126.1 (ArCH), 125.4 (C-2 or C-3),
H, 1ϫ 9-H), 4.83 (d, J = 11.0 Hz, 1 H, 1ϫ OCH2Ph), 4.72–4.63
84.7 (C-5 or C-7), 84.3 (C-6), 80.1 [C(CH3)3], 78.9 (C-5 or C-7),
Eur. J. Org. Chem. 2010, 3337–3344
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3341

P. Moosophon, M. C. Baird, S. Kanokmedhakul, S. G. Pyne
FULL PAPER
74.8 (OCH2Ph), 74.7 (OCH2Ph), 72.2 (OCH2Ph-6), 67.2 (C-4), 57.4
(C-1), 49.4 (NCH2), 28.2 (CH3), 28.5 (rotamer CH3) ppm.
(ArCH), 82.8 (C-6), 81.9 (C-5), 79.1 (C-7), 74.0 (OCH2Ph), 73.7
(2ϫ OCH2Ph), 68.1 (C-4), 57.5 (C-1), 51.2 (NCH2) ppm.
tert-Butyl (1R,2Z,4S,5R,6R,7R)-N-Benzyl-5,6,7-tris(benzyloxy)-4-
hydroxycyclohept-2-enylcarbamate (22): To a solution of 16
(23.8 mg, 0.032 mmol) in anhydrous CH2Cl2 (1.58 mL) was added
10 mol-% Grubbs’ 2nd generation catalyst (2.73 mg, 0.003 mmol).
The mixture was subjected to microwave irradiation in a sealed
tube in a CEM Discover microwave reactor at 90 °C, 100 W and
100 psi for 2ϫ2 h. Another 10 mol-% Grubbs’ 2nd generation cat-
alyst (2.73 mg, 0.003 mmol) was added, and the mixture subjected
to microwave irradiation for another 2 h. The product was purified
by column chromatography [EtOAc/petroleum ether (5:95 to
15:85)] to give 22 as a colourless oil in 37 % yield (7.6 mg,
0.012 mmol). Decomposition occurred to a large extent. Rf = 0.30
[EtOAc/petroleum ether (20:80)]. LRMS (ESI): m/z (%) = 635.6
(39) [M + H]+. HRMS (ESI): m/z = 636.3325 [M + H]+, calcd. for
tert-Butyl (1E,3R,4R,5R,6S)-N-Benzyl-4,5,6-tris(benzyloxy)-7-oxo-
1-phenylnona-1,8-dien-3-ylcarbamate (18): To a solution of 16
(161.2 mg, 0.218 mmol) in dry CH2Cl2 (5.4 mL) was added Dess–
Martin periodinane (120.3 mg, 0.284 mmol), and the mixture was
stirred at room temp. under N2 for 2 h. The mixture was then di-
luted with diethyl ether (5 mL) and the reaction quenched with
saturated NaHCO3 solution (5 mL) and Na2S2O3 (1 g). The prod-
uct was extracted with diethyl ether (3ϫ20 mL), and the combined
organic extracts were washed with saturated NaHCO3 solution
(40 mL), then H2O (40 mL) and dried (MgSO4). The crude product
was purified by column chromatography [EtOAc/petroleum ether
(0:100 to 10:90)] to give 18 as a clear oil in 79% yield (126.9 mg,
0.172 mmol). Rf = 0.41 [EtOAc/petroleum ether (20:80)]. LRMS
(ESI): m/z (%) = 737.5 (28) [M + H]+, 754.5 (100) [M + NH3].
HRMS (ESI): m/z = 738.3784 [M + H]+, calcd. for C48H52NO6
C H NO 636.3325. IR: νmax = 3339, 2981, 1080, 1050, 884 cm–1.
˜
40 46
6
[α]2D2 = +40.8 (c = 0.41, CHCl3). 1H NMR (500 MHz, CDCl3): δ =
7.36–7.2 (m, 16 H, 16 ϫ ArCH), 7.19 (t, J = 7.0 Hz, 2 H, 2 ϫ
ArCH), 7.12 (d, J = 7.0 Hz, 2 H, 2ϫ ArCH), 5.69 (br. d, 1 H, 2-
H), 5.48 (d, J = 11.5 Hz, 1 H, 3-H), 5.07 (d, J = 11.5 Hz, 1 H, 1ϫ
OCH2Ph), 4.97 (apparent d, J = 10.5 Hz, 2 H, 1-H and 1 ϫ
OCH2Ph), 4.81 (m, 2 H, 2ϫ OCH2Ph), 4.59 (d, J = 10.5 Hz, 1 H,
1ϫ OCH2Ph), 4.50–4.47 (br. m, 3 H, 1ϫ OCH2Ph and 2ϫ NCH2),
4.18 (m, 2 H, 4α-H and CHOBn), 3.74 (s, 2 H, 2ϫ CHOBn), 3.19
(s, 1 H, OH), 1.27 (s, 9 H, 9ϫ CH3), 1.44 (rot. CH3) ppm. 13C
NMR (125 MHz, CDCl3): δ = 151.6 (C=O), 140.2 (ArC), 138.6
(ArC), 138.0 (ArC), 131.3 (C-2 or C-3), 128.6 (ArCH), 128.5
(ArCH), 128.3 (ArCH), 128.1 (ArCH), 128.0 (ArCH), 127.8
(ArCH), 127.6 (ArCH), 126.3 (ArCH), 125.9 (C-2 or C-3), 125.6
(ArCH), 86.8 (CHOBn), 82.5 (CHOBn), 80.6 (CHOBn), 76.0
(OCH2Ph), 74.2 (OCH2Ph), 74.1 (OCH2Ph), 70.5 (C-4), 55.7 (C-
1), 48.2 (NCH2), 28.2 (CH3) ppm. Compound 22 was also prepared
from a solution of 19 (6.5 mg, 0.010 mmol) in anhydrous methanol
(0.78 mL), to which was added CeCl3·7H2O (3.8 mg, 0.010 mmol),
then NaBH4 (0.39 mg, 0.010 mmol); the mixture was then stirred
at room temp. under N2 for 20 min. The reaction was quenched
with H2O, the mixture extracted with CH2Cl2 (3ϫ5 mL) and dried
(MgSO4). The solvent was removed in vacuo to give 22 as a colour-
less oil in 65% yield (4.2 mg, 0.007 mmol).
738.3795. IR: νmax = 3385, 3027, 2976, 1689, 1455, 1162, 1072 cm–1.
˜
1
[α]2D2 = –52.2 (c = 1.25, CHCl3). H NMR (500 MHz, CDCl3): δ =
7.36–7.17 (m, 20 H, 20ϫ ArCH), 7.16–7.09 (m, 4 H, 4ϫ ArCH),
7.06 (m, 1 H, 1ϫ ArCH), 6.84 (dd, J = 17.0, 11.0 Hz, 1 H, 8-H),
6.33 (d, J = 17.0 Hz, 2 H, 2-H and 1ϫ 9-H), 6.15 (br. s, 1 H, 1-
H), 5.64 (d, J = 10.0 Hz, 1 H, 1ϫ 9-H), 4.76 (m, 1 H, 3-H), 4.64
(d, J = 11.5 Hz, 1 H, 1ϫ OCH2Ph), 4.58–4.52 (m, 5 H, 4ϫ
OCH2Ph and 1ϫ NCH2), 4.48 (m, 1 H, 1ϫ NCH2), 4.43 (d, J =
11.5 Hz, 1 H, 1ϫ OCH2Ph), 4.31 (t, J = 5.5 Hz, 1 H, 4-H), 4.28
(d, J = 4.0 Hz, 1 H, 6-H), 3.98 (br. s, 1 H, 5-H), 4.05 (rot., 5-H),
1.40 (s, 9 H, 9ϫ CH3), 1.42 (rot. CH3) ppm. 13C NMR (125 MHz,
CDCl3): δ = 200.5 (C-7), 155.4 (ArC), 139.4 (ArC), 138.3 (ArC),
138.1 (ArC), 137.4 (ArC), 136.8 (ArC), 135.2 (ArC), 132.5 (C-8),
128.9 (ArCH), 128.6 (ArCH), 128.5 (ArCH), 128.4 (ArCH), 128.3
(ArCH), 128.25 (ArCH), 128.20 (ArCH), 128.1 (ArCH), 128.0
(ArCH), 127.93 (ArCH), 127.86 (ArCH), 127.55 (ArCH), 127.48
(ArCH), 127.3 (ArCH), 126.9 (ArCH), 126.6 (ArCH), 126.4
(ArCH), 125.1 (C-2), 115.3 (C-9), 83.7 (C-6), 81.1 (C-5), 80.5 (C-
4), 80.2 [C(CH3)3], 73.9 (OCH2Ph), 73.5 (OCH2Ph), 72.9
(OCH2Ph), 59.8 (C-3), 49.7 (NCH2), 28.4 (CH3) ppm.
Benzyl[(1R,2Z,4R,5R,6R,7R)-5,6,7-tris(benzyloxy)-4-hydroxycyclo-
hept-2-enyl]amine (21): To a solution of 17 (58.7 mg, 0.092 mmol)
in MeOH (2.45 mL) was added concentrated HCl (0.54 mL) drop-
wise, and the mixture was stirred at room temp. for 18 h. The reac-
tion mixture was basified with NH3 (1.5 mL) and extracted with
CH2Cl2 (2ϫ25 mL). The combined organic extracts were dried
(Na2CO3), and the solvent was removed in vacuo. Purification by
column chromatography [EtOAc/petroleum ether (0:100 to 60:40)]
gave 21 as a colourless oil in 61% yield (30.4 mg, 0.057 mmol). Rf
= 0.41 (EtOAc). LRMS (ESI): m/z (%) = 535.7 (13) [M + H]+.
HRMS (ESI): m/z = 536.2774 [M + H]+, calcd. for C35H38NO4
Benzyl[(1R,2Z,4S,5R,6R,7R)-5,6,7-tris(benzyloxy)-4-hydroxycyclo-
hept-2-enyl]amine (23): The title compound was prepared according
to the method described for the synthesis of 21 by using 22 (3.1 mg,
0.0049 mmol) as starting material to give 23 as a colourless oil in
54% yield (1.4 mg, 0.003 mmol). Rf = 0.67 (EtOAc). LRMS (ESI):
m/z (%) = 535.9 (100) [M + H]+. HRMS (ESI): m/z = 536.2780 [M
+ H]+, calcd. for C35H38NO4 536.2801. [α]2D5 = +56.7 (c = 0.07,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = (m, 20 H, 20ϫ ArCH),
5.80 (ddd, J = 11.0, 3.5, 2 Hz, 1 H, 3-H), 5.57 (br. d, J = 11.5 Hz,
1 H, 2-H), 4.98 (d, J = 10.5 Hz, 1 H, 1ϫ COCH2-5), 4.96 (d, J =
10.5 Hz, 1 H, 1ϫ OCH2Ph-7), 4.77 (d, J = 12.0 Hz, 1 H, 1ϫ
OCH2Ph-6), 4.75 (d, J = 11.5 Hz, 1 H, 1ϫ OCH2Ph-7), 4.71 (d, J
= 12.0 Hz, 1 H, 1ϫ OCH2Ph-6), 4.61 (d, J = 11.0 Hz, 1 H, 1ϫ
536.2801. IR: ν
= 3050, 2914, 2843, 1650, 1496, 1450, 1068,
˜
max
1028 cm–1. [α]2D5 = –47.8 (c = 0.25, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = (m, 20 H, 20ϫ ArCH), 5.74 (dd, J = 12.0, 5.5 Hz, 1
H, 3-H), 5.69 (dd, J = 12.0, 3.5 Hz, 1 H, 2-H), 4.90 (d, J = 12.0 Hz,
1 H, 1ϫ OCH2Ph-7), 4.77 (d, J = 11.5 Hz, 1 H, 1ϫ OCH2Ph-5), OCH2Ph-5), 4.09 (d, J = 8.5 Hz, 1 H, 4-H), 4.01 (s, 1 H, 7-H), 3.73
4.72 (m, 4 H, 2ϫ OCH2Ph-6, 1ϫ OCH2Ph-7 and 4-H), 4.63 (d, J
= 12.0 Hz, 1 H, 1ϫ OCH2Ph-5), 4.10 (br. s, 1 H, 7-H), 3.94 (dd, J
(apparent t, J = 8.5 Hz, 1 H, 5-H), 3.65 (d, J = 13.0 Hz, 1 H, 1ϫ
NCH2), 3.54 (d, J = 13.0 Hz, 1 H, 1ϫ NCH2), 3.54 (d, J = 9.5 Hz,
= 7.5, 2.5 Hz, 1 H, 5-H), 3.89 (d, J = 7.5 Hz, 1 H, 6-H), 3.66 (d, J 1 H, 6-H), 3.16 (s, 1 H, 1-H) ppm. 13C NMR (125 MHz, CDCl3):
= 13.5 Hz, 1 H, 1ϫ NCH2), 3.62 (d, J = 13.5 Hz, 1 H, 1ϫ NCH2),
δ = 138.2 (ArC), 131.5 (C-2), 131.4 (C-3), 128.6 (ArCH), 128.5
(ArCH), 128.4 (ArCH), 128.04 (ArCH), 128.02 (ArCH), 127.95
3.46 (br. s, 1 H, 1-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 140.2
(ArC), 138.9 (ArC), 138.5 (ArC), 138.3 (ArC), 134.1 (C-2), 129.4 (ArCH), 127.85 (ArCH), 127.81 (ArCH), 127.7 (ArCH), 127.6
(C-3), 128.43 (ArCH), 128.41 (ArCH), 128.35 (ArCH), 128.29 (ArCH), 127.0 (ArCH), 86.2 (C-6), 80.6 (C-5), 79.1 (C-7), 75.9
(ArCH), 128.0 (ArCH), 127.95 (ArCH), 127.94 (ArCH), 127.86 (OCH2Ph-5), 73.8 (OCH2Ph-7), 73.7 (OCH2Ph-6), 70.3 (C-4), 57.5
(ArCH), 127.8 (ArCH), 127.7 (ArCH), 127.6 (ArCH), 126.8
(C-1), 51.2 (NCH2) ppm.
3342
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3337–3344

Total Synthesis of Calystegine B4
1
tert-Butyl (1R,2Z,5S,6R,7R)-N-Benzyl-5,6,7-tris(benzyloxy)-4-oxo-
0.023 mmol) in 92–95% purity as judged by H NMR analysis. Rf
cyclohept-2-enylcarbamate (19): To a solution of 17 (28.2 mg, = 0.17 [MeOH/EtOAc/NH3 (8.5:1:0.5)]. LRMS (ESI): m/z (%) =
0.044 mmol) in dry CH2Cl2 (1.1 mL) was added Dess–Martin 175.9 (100) [M + H]+. HRMS (ESI): m/z = 176.0918 [M + H]+,
periodinane (24.5 mg, 0.058 mmol), and the mixture was stirred at
room temp. under N2 for 30 min. The mixture was then diluted
with diethyl ether (1 mL) and the reaction quenched with saturated
NaHCO3 solution (1 mL) and Na2S2O3 (200 mg). The product was
extracted with diethyl ether (3ϫ15 mL) and the combined organic
calcd. for C7H14NO4 176.0923. IR: ν
= 3283, 2899, 1668,
˜
max
1585 cm–1. [α]1D9 = –29.5 (c = 0.185, H2O); ref.[1c] [α]D = –63.0 (c =
0.65, H2O). 1H NMR {500 MHz, [D4]pyridine/D2O (4:1)}: δ = 4.35
(d, J = 9.0 Hz, 1 H, 2-H), 4.06 (dd, J = 9.0, 4.5 Hz, 1 H, 3-H), 4.03
(d, J = 3.0 Hz, 1 H, 4-H), 3.72 (dd, J = 8.0, 2.5 Hz, 1 H, 5-H), 2.42
extracts were washed with saturated NaHCO3 solution (40 mL), (ddd, J = 12.8, 10.0, 4.5 Hz, 1 H, 7α-H), 2.21 (tdd, J = 12.8, 4.5,
then H2O (40 mL) and dried (MgSO4). The crude product was
purified by column chromatography [EtOAc/petroleum ether
(10:90)] to give 19 as a colourless oil in 80% yield (22.4 mg,
0.035 mmol). Rf = 0.40 [EtOAc/petroleum ether (20:80)]. LRMS
(ESI): m/z (%) = 633.7 (100) [M + H]+. HRMS (ESI): m/z =
3.0 Hz, 1 H, 6β-H), 1.97 (tdd, J = 12.5, 4.5, 1.5 Hz, 1 H, 7β-H),
1.36 (ddd, J = 13.3, 10.0, 5.0 Hz, 1 H, 6α-H) ppm; the H NMR
1
spectroscopic data agree with that in the literature except for the
multiplicity of the signal for 4-H, which was published as a dd
signal.[1c] 13C NMR (125 MHz, D2O): δ = 90.3 (C-1), 77.3 (C-2),
72.6 (C-4), 71.6 (C-3), 56.9 (C-5), 27.6 (C-7), 22.9 (C-6) ppm; all
peaks are 2.2 ppm upfield, except that for C-2 (δ =2.3 ppm), from
634.3137 [M + H]+, calcd. for C40H44NO6 634.3169. IR: ν
=
˜
max
2917, 2848, 1686, 1454, 1058, 733 cm–1. [α]2D2 = –119.2 (c = 0.85,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.34–7.24 (m, 15 H, literature values for the natural product;[1c] the signal for C-1 was
15ϫ ArCH), 7.19–7.15 (m, 3 H, 3ϫ ArCH), 7.08 (d, J = 7.0 Hz, not observed in the 13C NMR spectrum but was able to be deter-
2 H, 2ϫ ArCH), 5.98 (d, J = 13.0 Hz, 1 H, 3-H), 5.88 (d, J =
13.5 Hz, 1 H, 2-H), 5.12 (s, 1 H, 1-H), 4.87 (d, J = 11.5 Hz, 1 H,
1ϫ OCH2Ph-7), 4.71 (d, J = 9.0 Hz, 1 H, 1ϫ OCH2Ph-5), 4.70
(m, 2 H, 2ϫ OCH2Ph-6), 4.53 (d, J = 11.5 Hz, 1 H, 1ϫ OCH2Ph-
5), 4.49 (d, J = 11.5 Hz, 1 H, OCH2Ph-7), 4.44 (d, J = 17.0 Hz, 1
H, 1ϫ NCH2), 4.36 (s, 1 H, 7-H), 4.28 (d, J = 17.0 Hz, 1 H, 1ϫ
mined from the gHMBC spectrum.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of compounds, 1, 3–
7 and 9–16.
NCH2), 4.17 (s, 1 H, 5-H or 6-H), 3.96 (d, J = 6.5 Hz, 1 H, 5-H Acknowledgments
or 6-H), 3.86 (rot. 5-H or 6-H), 1.28 (s, 9 H, 9ϫ CH3), 1.40 (rot.
CH3), 4.78 (rot. m, 1 H), 4.64 (rot. m, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 195.8 (C-4), 155.6 (C=O), 140.3 (ArC),
138.1 (ArC), 137.3 (ArC), 136.3 (C-2), 130.5 (C-3), 128.4 (ArCH),
128.2 (ArCH), 128.14 (ArCH), 128.06 (ArCH), 127.8 (ArCH),
127.7 (ArCH), 127.6 (ArCH), 126.3 (ArCH), 125.9 (ArCH), 86.4
(C-5 or C-6), 82.8 (C-5 or C-6), 80.7 (C-7), 80.5 [C(CH3)3], 73.6
(OCH2Ph-7), 73.0 (OCH2Ph-5 or -6), 72.7 (OCH2Ph-5 or -6), 58.5
(C-1), 49.4 (NCH2), 28.1 (CH3), 28.4 (rot. CH3) ppm. Compound
19 was also prepared in 57% yield (5.3 mg, 0.0084 mmol) according
to the method described for 17 by using 18 (10.9 mg, 0.015 mmol)
and ca. 20 mol-% Grubbs’ 2nd generation catalyst (2.52 mg,
0.003 mmol).
We thank the Australian Research Council and the University of
Wollongong for financial support and the Development and Pro-
motion of Science and Technology Talents Project (DPST) of Thai-
land for a PhD scholarship to P. M.
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A-26(OH) as resin. The resin was first washed with H2O, basified
with NH3 and then neutralised with H2O. The product was eluted
with H2O to give 20 as a white solid in 51% yield (4.0 mg,
Eur. J. Org. Chem. 2010, 3337–3344
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3343

P. Moosophon, M. C. Baird, S. Kanokmedhakul, S. G. Pyne
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Received: February 4, 2010
Published Online: May 4, 2010
3344
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3337–3344