Total synthesis of noricumazole B establishes D-arabinose as glycan unit

Article abstract of DOI:10.1039/c2ob26256h

The total synthesis of noricumazole B, a secondary metabolite from myxobacteria, was achieved. It established the glycan moiety to be D-α-arabinoside.

Full text of DOI:10.1039/c2ob26256h

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PAPER
Total synthesis of noricumazole B establishes D-arabinose as glycan unit†
Jenny Barbier,a Klaus Gerth,b Rolf Jansenb and Andreas Kirschning*a
Received 2nd July 2012, Accepted 21st August 2012
DOI: 10.1039/c2ob26256h
The total synthesis of noricumazole B, a secondary metabolite from myxobacteria, was achieved.
It established the glycan moiety to be D-α-arabinoside.
not a proof and does not disclose whether the glycan moiety is
Introduction
D- or L-arabinose. Thus, based on our earlier synthetic work1
Noricumazole A (1a) and the related icumazole A (2a) are iso-
lates from the myxobacterium Sorangium cellulosum and the
structures including all stereogenic centers were established by
spectroscopic methods and finally by total synthesis (Fig. 1).1
Noricumazole A (1a) is only one representative of a small
family of analogues isolated from myxobacteria. Additionally,
we reported on the isolation of noricumazole B (1b) and noricu-
mazole C (1c) that are glycosylated derivatives at C-11 and
C-18, respectively. Likewise, along with icumazole A (2a), we
also described icumazole B1 (2b) and B2 (2c).1 Preliminary bio-
logical screening revealed that noricumazole A (1a) is the first
natural product reported so far that shows a stabilizing effect on
the tetrameric architecture of the potassium channel KcsA
thereby blocking it (1–4 μM)1 and that shows anti-HCV
activity.2
which included the preparation of a small compound library
derived from noricumazole A,2 we now report on the total syn-
thesis of noricumazole B (1b) and prove that its glycan moiety is
α-D-arabinose. The major new issues we had to consider were
orthogonal protection of the carbinol groups at C-18 and C-20,
the timing of glycosylation and the choice of the glycosyl donor.
Results and discussion
The principal retrosynthetic plan, that is depicted in Scheme 1,
relies on our successful total synthesis of noricumazole A (1a).1
During our studies on the structure elucidation of this new
group of secondary metabolites from myxobacteria, we proposed
that the glycan moiety in noricumazole B is an α-linked arabi-
nose. This suggestion was based on the following data. The gly-
cosylation site at C-18 was located from correlations in the
HMBC spectrum between the anomeric methine C-1′ and the
1
oxymethine C-18. Based on a comparison of H and 13C NMR
data of 1b with the literature values, we proposed an α-arabino-
furanosyl residue.3 Firstly, the α-arabino-furanosyl configuration
was assigned from 13C-NMR fingerprint chemical shift values
(δ)1 and secondly from the small coupling constants J1,2 = 1.5 Hz
and J2,3 = 3.7 Hz and a coupling constant of J = 5.9 Hz
between H3′ and H4′ which we interpreted to be a trans
orientation.4
Fig. 1 Noricumazoles A–C (1a–c) and icumazoles A–C (2a–c) (num-
bering does not relate to IUPAC; however for clarity reasons the depicted
numbering was chosen in this report).
These data and rationales can be regarded as a strong indi-
cation for the nature of the glycan unit. However, it is definitely
aInstitut für Organische Chemie and Biomolekulares Wirkstoffzentrum
(BMWZ), Leibniz Universität Hannover, Schneiderberg 1b, 30167
Hannover, Germany. E-mail: andreas.kirschning@oci.uni-hannover.de;
Fax: +49 (0)511-7623011; Tel: +49 (0)511-7624614
bHelmholtz Zentrum für Infektionsforschung (HZI), Inhoffenstrasse 7,
38124 Braunschweig, Germany
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26256h
Scheme 1 Retrosynthetic plan.
8298 | Org. Biomol. Chem., 2012, 10, 8298–8307
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Scheme 2 Synthesis of vinyliodide 9.
Scheme 4 Finalisation of total synthesis.
The free hydroxyl groups in carbinol 15a were protected as
acetates which was followed by desilylation to yield compound
16a. As a by-product TBS- and PMB-deprotected acetate 17a
was isolated. In order to determine the influence of the stereo-
genic center at C-11 on the biological activity also the epimer
15b was deprotected and compared to noricumazole B 1b
(Scheme 4).
Different glycosylation protocols were probed including the
use of thioglycosides11 activated with the reagent systems N-
iodo succinimide/AgOTf12 or 1-benzenylsulfinylpiperidine
(BSP) and tri-tert-butylpyrimidine (TTBP),13 all of which either
gave the desired glycosidation product in low yield or not at all
or alternatively led to bis-glycosylation at C-9 as well as at C-11.
Obviously, the PMB group is prone to cleavage under these elec-
trophilic activating conditions. Finally, a modification of the
Koenigs–Knorr method under Helferich-type conditions14,15
using commercially available per-O-benzylated bromo arabinose
18 was found to be suited to finalise the synthesis of noricuma-
zole B 1b after global deprotection in a very mild way.16 Noricu-
mazole B was obtained in 4% overall yield over 19 steps
(longest linear sequence) (including Mitsunobu inversion: 21
steps and 6% overall yield).
Scheme 3 Coupling of western and eastern fragments 4 and 9 and
Mitsunobu inversion.
The synthesis of the eastern fragment started from the published
Masamune anti-aldol product 55 which was O-protected and
transformed into the orthogonally protected carboxylate 7 by
several standard steps of which the Nagao-aldol reaction6 was
the key step. Coupling with serine-methylester and ring closure
gave oxazolidine which was oxidised to oxazole 8 following
Barrish and Singh’s procedure.7 Then, the ester was transformed
into the homologised vinyliodide 9 by transferring the intermedi-
ate aldehyde into the alkyne using the Bestmann–Ohira reagent
138 followed by a hydrozirconation and by ipso-iodination.9
The western aldehyde 4 was obtained according to our earlier
reports1 so that it could be directly coupled with vinyliodide 9
through vinylzinc addition to aldehyde 4 (Scheme 2). Both epi-
meric carbinols 15a and 15b were formed as a 1 : 1 mixture and
were separated by chromatography. Conversion of the undesired
coupled product 15b into the desired compound 15a was
achieved by Mitsunobu inversion10 followed by ester hydrolysis
which led to an increase of the yield from 33% to 59% in favour
of the desired carbinol 15a after coupling (Scheme 3).
Conclusions
In summary, the present work discloses the total synthesis of
noricumazole B, a secondary metabolite from myxobacterium
Sorangium cellulosum, thereby establishing the complete
structure of noricumazole B whose aglycon is identical to
noricumazole A. We demonstrated that the glycan moiety is an
α-D-arabino furanose.
This journal is © The Royal Society of Chemistry 2012
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THF (100 mL) was added DIBAL-H (1.0 mol L−1 in hexane,
44 mL, 44.0 mmol, 3.0 equiv.) at −78 °C. After 1 h, the reaction
mixture was warmed up to −20 °C. After 2 h a sat. aq. solution
of Rochelle’s salt was added and the mixture was stirred for
30 min at room temperature. After extraction with CH2Cl2 the
combined organic extracts were dried over MgSO4 and concen-
trated under reduced pressure. Purification by flash chromato-
graphy (petroleum ether–ethyl acetate = 5 : 1) furnished alcohol
S1 as a colorless oil (3.2 g, 13.4 mmol, 91%).
Experimental
General remarks
1H and 13C NMR spectra were recorded with Bruker DPX-400,
AVANCE-400 and DRX-500. The numbering of the protons
relates to the numbering chosen in Fig. 1. High resolution mass
spectra were obtained with a Micromass LCT via loop-mode
injection from a Waters (Alliance 2695) HPLC system. Alterna-
tively a Micromass Q-TOF in combination with a Waters Aquity
Ultraperformance LC system was employed. Ionization was
achieved by ESI or APCI. Modes of ionization, calculated and
found mass are given. RP-HPLC was performed on RP-CN with
CH3CN–H2O gradient elution. CD spectra were obtained using a
Jasco J-810 circular dichroism spectropolarimeter. Analytical
thin-layer chromatography was performed using precoated silica
gel 60 F254 plates (Merck, Darmstadt). Flash column chromato-
graphy was performed on Merck silica gel (230–400 mesh).
Unless otherwise noted, all reactions were carried out under an
atmosphere of nitrogen in dry glassware. Commercially available
reagents and dry solvents were used as received.
1
[α]2D0 = −39.8 (c 1.0, CDCl3); H-NMR (400 MHz, CDCl3,
CHCl3 = 7.26 ppm) δ 7.26 (d, J = 8.5 Hz, 2H, PMB), 6.88 (d,
J = 8.5 Hz, 2H, PMB), 4.56 (d, J = 10.9 Hz, 1H, PMB), 4.37 (d,
J = 10.9 Hz, 1H, PMB), 3.80 (s, 3H, PMB), 3.64 (dd, J = 10.9,
3.8 Hz, 1H, H-18), 3.55 (dd, J = 10.9, 6.9 Hz, 1H, H-18′), 3.35
(ddd, J = 6.9, 4.8, 4.8 Hz, 1H, H-20), 2.69 (bs, 1H, OH), 1.90
(dsext, J = 6.9, 3.8 Hz, 1H, H-19), 1.74 (ddddd, J = 14.7, 7.5,
7.5, 7.5, 4.8 Hz, 1H, H-21), 1.60 (ddddd, J = 14.7, 7.5, 7.5, 7.5,
4.8 Hz, 1H, H-21′), 0.93 (t, J = 7.5 Hz, 3H, H-22), 0.89 (d, J =
6.9 Hz, 3H, H-23) ppm; 13C-NMR (100 MHz, CDCl3, CDCl3 =
77.0 ppm) δ 159.2 (q, PMB), 130.3 (q, PMB), 129.4 (2×
t, PMB), 113.9 (2× t, PMB), 84.7 (t, C-20), 71.2 (s, PMB),
67.0 (s, C-18), 55.2 (p, PMB), 37.1 (t, C-19), 23.0 (s,
C-21), 14.1 (t, C-23), 8.3 (p, C-22); HRMS (ESI): m/z: calcu-
lated for C14H22O3Na: 261.1467 [M + Na]+, found: 261.1471
[M + Na]+.
Masamune ester 6. To a solution of alcohol 55 (11.3 g,
21.0 mmol, 1.0 equiv.) in CH2Cl2 (250 mL) were sequentially
added 4-methoxybenzyl 2,2,2-trichloroacetimidate (13.1 g,
46.5 mmol, 2.2 equiv.) and camphor-10-sulfonic acid (0.9 g,
3.7 mmol, 0.2 equiv.) at room temperature. The reaction mixture
was stirred for 16 h at room temperature and terminated by
addition of sat. aq. NaHCO3 solution. The mixture was extracted
with CH2Cl2 and the combined organic extracts were dried over
MgSO4. The solvent was removed under reduced pressure and
the residue was purified by flash chromatography (petroleum
ether–ethyl acetate = 10 : 1 → 3 : 1) to furnish the PMB-ether 6
as a light yellow oil (19.4 g, 29.6 mmol, quant).
(2S,3R)-3-(4-Methoxybenzyloxy)-2-methylpentanal (S2). To a
solution of carbinol S1 (1.6 g, 6.5 mmol, 1.0 equiv.) in CH2Cl2
(120 mL) were sequentially added NaHCO3 (2.7 g, 32.5 mmol,
5.0 equiv.) and Dess–Martin periodinane (4.1 g, 9.8 mmol, 1.5
equiv.) at room temperature. After 30 min, the reaction was ter-
minated by addition of a sat. aq. Na2S2O3 solution and the
aqueous layer was extracted with CH2Cl2. The combined organic
extracts were dried over MgSO4 and concentrated under reduced
pressure. The crude aldehyde S2 was used in the next step
without further purification.
[α]2D5 = +35.0 (c 1.0, CDCl3); H-NMR (400 MHz, CDCl3,
1
CHCl3 = 7.26 ppm) δ 7.35–7.08 (m, 12H, Bn, Mes, Ph), 6.79
(d, J = 7.9 Hz, 2H, PMB), 6.74 (d, J = 7.9 Hz, 2H, PMB), 5.72
(d, J = 4.4 Hz, 1H, OCHPh), 4.69 (d, J = 16.0 Hz, 1H, Bn), 4.42
(d, J = 11.0 Hz, 1H, PMB), 4.41 (d, J = 16.0 Hz, 1H, Bn), 4.38
(d, J = 11.0 Hz, 1H, PMB), 3.97 (dddd, J = 7.1, 7.1, 7.1, 4.4 Hz,
1H, H-9), 3.77 (s, 3H, PMB), 3.64 (ddd, J = 7.5, 6.4, 3.7 Hz,
1H, H-8), 2.75 (quin, J = 7.5 Hz, 1H, H-19), 2.46 (s, 6H, Mes),
2.30 (s, 3H, Mes), 1.60 (dddd, J = 14.0, 7.3, 7.3, 3.7 Hz, 1H,
H-21), 1.48 (dddd, J = 14.0, 7.3, 7.3, 6.4 Hz, 1H, H-21′), 1.07
(d, J = 7.5 Hz, 3H, H-23), 1.03 (d, J = 7.1 Hz, 3H, NCHCH3),
0.91 (t, J = 7.3 Hz, 3H, H-22) ppm; 13C-NMR (100 MHz,
CDCl3, CDCl3 = 77.0 ppm) δ 173.7 (q, C-18), 159.1 (q, PMB),
142.4 (q, Mes), 140.3 (q, Ph), 138.9 (q, Mes), 138.5 (q, Mes),
133.5 (q, Mes), 132.1 (2× t,), 130.5 (q, Bn), 129.4 (2× t, PMB),
129.3 (2× t, Bn), 129.26 (2× t, Mes), 128.3 (t, Ph), 128.2 (t, Ph),
127.9 (2× t, Bn), 127.7 (t, Ph), 127.0 (t, Bn), 125.9 (2× t, Ph),
113.7 (2× t, PMB), 80.6 (t, C-20), 77.9 (t, OCHPh), 71.4 (s,
PMB), 56.8 (t, NCCH3), 55.3 (p, PMB), 48.1 (s, Bn), 42.8 (t,
C-19), 29.7 (s, C-21), 22.3 (2× p, Mes), 20.9 (p, Mes), 13.6 (p,
C-23), 12.6 (p, NCCH3), 8.3 (p, C-22) ppm; HRMS (ESI): m/z:
calculated for C39H47NO6SNa: 680.3022 [M + Na]+, found:
680.3016 [M + Na]+.
(3S,4R,5R)-3-(tert-Butyldimethylsilyloxy)-1-[(R)-4-isopropyl-2-
thioxothiazolidin-3-yl]-5-(4-methoxybenzyloxy)-4-methylheptan-
1-one (S3). TiCl4 (1.3 mL, 11.7 mmol, 1.8 equiv.) was added to
a solution of 1-[(R)-4-isopropyl-2-thioxothiazolidin-3-yl]etha-
none (11)6 (2.3 g, 11.1 mmol, 1.7 equiv.) in CH2Cl2 (250 mL) at
−50 °C. After stirring for 20 min DIPEA (1.9 mL, 11.7 mmol,
1.8 equiv.) was added to the reaction mixture. After stirring for
2 h at −40 °C the reaction mixture was cooled to −78 °C and
aldehyde S2 (1.5 g, 6.5 mmol, 1.0 equiv.) in CH2Cl2 (80 mL)
was added. After 2 h the reaction was terminated by addition of
a sat. aq. NH4Cl solution and was warmed up to room tempera-
ture. The aqueous layer was extracted with CH2Cl2 and the com-
bined organic extracts were dried over MgSO4 and concentrated
under reduced pressure to furnish the crude product as an orange
oil.
This material was dissolved in CH2Cl2 (250 mL) and 2,6-luti-
dine (1.3 mL, 11.4 mmol, 1.8 equiv.) as well as TBSOTf
(2.1 mL, 9.1 mmol, 1.4 equiv.) were sequentially added at
−78 °C. The mixture was warmed to room temperature and
stirred for 3 h. The reaction was terminated by addition of a sat.
aq. NH4Cl solution and extracted with CH2Cl2. The combined
organic extracts were dried over MgSO4 and concentrated under
(2S,3R)-3-(4-Methoxybenzyloxy)-2-methylpentan-1-ole
To a solution of PMB-ether 6 (9.7 g, 14.7 mmol, 1.0 equiv.) in
(S1).
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(R)-Methyl-2-[(3S,4R,5R)-3-(tert-butyldimethylsilyloxy)-5-(4-
methoxybenzyloxy)-4-methylheptanamido]-3-hydroxypropano-
ate (S4). To a solution of TBTU (103 mg, 0.3 mmol, 1.0 equiv.)
and HOBt (49 mg, 0.3 mmol, 1.0 equiv.) in CH2Cl2 (2 mL)
were sequentially added acid 7 (132 mg, 0.3 mmol, 1.0 equiv.)
in CH2Cl2 (2 mL) and DIPEA (0.2 mL, 1.0 mmol, 3.0 equiv.).
After stirring for 2 h at room temperature L-serine methyl ester
(12) (60 mg, 0.4 mmol, 1.2 equiv.) was added to the reaction
mixture and stirring was continued for 3 days at room tempera-
ture. The reaction was terminated by addition of a sat. aq. NH4Cl
solution and the aqueous layer was extracted with CH2Cl2. The
combined organic extracts were dried over MgSO4 and concen-
trated under reduced pressure. Purification by flash chromato-
graphy (petroleum ether–ethyl acetate = 3 : 1 → 1 : 1) furnished
amide S4 as a colorless solid (136 mg, 0.3 mmol, 83%).
reduced pressure. Purification by flash chromatography (pet-
roleum ether–ethyl acetate = 15 : 1) yields the TBS-PMB-ether
S3 as a yellow oil (3.5 g, 6.3 mmol, 97%).
1
[α]3D0 = −200.5 (c 2.0, CDCl3); H-NMR (400 MHz, CDCl3,
CHCl3 = 7.26 ppm) δ 7.28 (d, J = 8.7 Hz, 2H, PMB), 6.85 (d,
J = 8.7 Hz, 2H, PMB), 5.04 [pt, J = 6.6 Hz, 1H, CH(CH3)2],
4.69 (ddd, J = 9.2, 3.8, 2.2 Hz, 1H, H-18), 4.46 (d, J = 10.9 Hz,
1H, PMB), 4.35 (d, J = 10.9 Hz, 1H, PMB), 3.79 (s, 3H, PMB),
3.57 (dd, J = 17.1, 9.2 Hz, 1H, H-17), 3.46 (dd, J = 11.4, 6.6 Hz,
1H, SCH2), 3.20 (ddd, J = 7.7, 6.6, 3.9 Hz, 1H, H-20), 3.01
(dd, J = 11.4, 0.7 Hz, 1H, SCH2), 2.97 (dd, J = 17.1, 2.2 Hz,
1H, H-17′), 2.40 [psext, J = 6.6 Hz, 1H, CH(CH3)2], 1.95 (ddq,
J = 14.6, 6.6, 3.8 Hz, 1H, H-19), 1.70 (ddq, J = 14.6, 14.2,
3.9 Hz, 1H, H-21), 1.49 (ddq, J = 14.2, 7.7, 7.1 Hz, 1H, H-21′),
1.06 [d, J = 6.6 Hz, 3H, CH(CH3)2], 0.97 [d, J = 6.6 Hz, 3H,
CH(CH3)2], 0.93 (t, J = 7.1 Hz, 3H, H-22), 0.84 (s, 9H, TBS),
0.82 (d, J = 7.2 Hz, 3H, H-23), 0.08 (s, 3H, TBS), 0.02 (s, 3H,
TBS) ppm; 13C-NMR (100 MHz, CDCl3, CDCl3 = 77.0 ppm) δ
202.8 (q, CS2), 172.5 (q, NCO), 159.0 (q, PMB), 30.9 (q,
PMB), 129.4 (2× t, PMB), 113.7 (2× t, PMB), 80.7 (t, C-20),
71.7 (t, NCCH), 70.9 (s, PMB), 69.3 (t, C-18), 55.2 (p, PMB),
41.8 (t, C-19), 41.5 (s, C-17), 30.9 [t, CH(CH3)2], 30.8 (s,
SCH2), 25.8 (3× p, TBS), 23.1 (s, C-21), 19.2 [p, CH(CH3)2],
18.0 (q, TBS), 17.9 [p, CH(CH3)2], 10.7 (p, C-23), 8.7 (p,
C-22), −4.66 (p, TBS), −4.7 (p, TBS) ppm; HRMS (ESI): m/z:
calculated for C28H47NO4S2SiNa: 576.2614 [M + Na]+, found:
576.2604 [M + Na]+.
M.p. = 83–84 °C; [α]D20 = +7.0 (c 1.0, CDCl3); 1H-NMR
(400 MHz, CDCl3, CHCl3 = 7.26 ppm) δ 7.29 (d, J = 8.5 Hz,
2H, PMB), 7.11 (d, J = 7.3 Hz, 1H, NH), 6.86 (d, J = 8.5 Hz,
2H, PMB), 4.63 (ddd, J = 7.3, 3.9, 3.8 Hz, 1H, H-14), 4.43 (d, J
= 10.9 Hz, 1H, PMB), 4.41 (d, J = 10.9 Hz, 1H, PMB), 4.20 (q,
J = 5.9 Hz, 1H, H-18), 3.89 (dd, J = 11.0, 3.9 Hz, 1H, H-15),
3.81 (dd, J = 11.0, 3.8 Hz, 1H, H-15′), 3.79 (s, 3H, PMB), 3.74
(s, 3H, CH3O), 3.42 (ddd, J = 6.9, 6.7, 3.6 Hz, 1H, H-20), 2.55
(dd, J = 14.3, 5.9 Hz, 1H, H-17), 2.47 (bs, 1H, OH), 2.34 (dd, J
= 14.3, 5.9 Hz, 1H, H-17′), 2.13 (pdddd, J = 12.4, 6.7, 6.7,
5.9 Hz, 1H, H-19), 1.62 (ddddd, J = 14.4, 7.7, 7.3, 6.9, 3.6 Hz,
1H, H-21), 1.45 (dquin, J = 14.4, 6.8 Hz, 1H, H-21′), 0.92 (t, J
= 7.7 Hz, 3H, H-22), 0.90 (s, 9H, TBS), 0.85 (d, J = 6.8 Hz, 3H,
H-23), 0.08 (s, 3H, TBS), 0.07 (s, 3H, TBS) ppm; 13C-NMR
(100 MHz, CDCl3, CDCl3 = 77.0 ppm) δ 172.0 (q, C-16), 170.8
(q, C-13), 159.1 (q, PMB), 130.9 (q, PMB), 129.6 (2× t, PMB),
113.7 (2× t, PMB), 80.0 (t, C-20), 71.2 (t, C-18), 70.7 (s, PMB),
63.5 (s, C-15), 55.2 (p, PMB), 54.6 (t, C-14), 52.5 (p, CH3O),
41.4 (s, C-17), 39.9 (t, C-19), 25.8 (3× p, TBS), 22.4 (s, C-21),
18.0 (q, TBS), 11.7 (p, C-23), 8.7 (p, C-22), −4.5 (p, TBS),
−4.8 (p, TBS) ppm; HRMS (ESI): m/z: calculated for
C26H46NO7Si: 512.3044 [M + H]+, found: 512.3034 [M + H]+.
(3S,4R,5R)-3-(tert-Butyldimethylsilyloxy)-5-(4-methoxybenzyl-
oxy)-4-methylheptanoic acid (7). To a solution of S3 (198 mg,
0.4 mmol, 1.0 equiv.) in THF–H2O (4 : 1, 8.3 mL) were sequen-
tially added H2O2 (30%, 88 μL, 2.9 mmol, 8.0 equiv.) and 1 N
aqueous LiOH (1.4 mL, c = 1 mol L−1, 1.4 mmol, 4.0 equiv.) at
0 °C and the reaction mixture was allowed to warm to room
temperature. After 3 h, the reaction was terminated by addition
of a sat. aq. Na2S2O3 solution and H2O and the aqueous layer
was extracted with CH2Cl2. The combined organic extracts were
dried over MgSO4 and concentrated under reduced pressure.
Purification by flash chromatography (petroleum ether–ethyl
acetate = 5 : 1) furnished carboxylic acid 7 as a colorless oil
(132 mg, 0.5 mmol, 90%).
(R)-Methyl-2-[(2S,3R,4R)-2-(tert-butyldimethylsilyloxy)-4-(4-
methoxybenzyloxy)-3-methylhexyl]-4,5-dihydrooxazol-4-carboxy-
late (S5). To a solution of S4 (1.7 g, 3.2 mmol, 1.0 equiv.) in
CH2Cl2 (50 mL) was added DAST (0.5 mL, 3.9 mmol, 1.2
equiv.) at −78 °C. After stirring for 2 h at −78 °C K2CO3
(807 mg, 5.8 mmol, 1.8 equiv.) and a sat. aq. K2CO3 solution
were added and the reaction mixture was allowed to warm up to
room temperature. After extraction with CH2Cl2, the combined
organic extracts were dried over MgSO4 and concentrated under
reduced pressure. Purification by flash chromatography (pet-
roleum ether–ethyl amine = 4 : 1) furnished oxazolidine S5 as a
colorless oil (1.3 g, 2.7 mmol, 82%).
1
[α]2D3 = −22.3 (c 1.0, CDCl3); H-NMR (400 MHz, CDCl3,
CHCl3 = 7.26 ppm) δ 7.27 (d, J = 8.7 Hz, 2H, PMB), 6.86 (d, J
= 8.7 Hz, 2H, PMB), 4.48 (d, J = 11.1 Hz, 1H, PMB), 4.45 (dt,
J = 7.9, 4.2 Hz, 1H, H-18), 4.35 (d, J = 11.1 Hz, 1H, PMB),
3.79 (s, 3H, PMB), 3.23 (ddd, J = 7.5, 4.6, 4.2 Hz, 1H, H-20),
2.46 (dd, J = 15.0, 4.2 Hz, 1H, H-17), 2.39 (dd, J = 15.0,
7.9 Hz, 1H, H-17′), 1.98 (ddq, J = 7.9, 7.3, 4.2 1H, H-19), 1.69
(pdddd, J = 14.7, 14.5, 7.3, 4.6 Hz, 1H, H-21), 1.49 (pdddd, J =
14.5, 13.2, 7.5, 7.3 Hz, 1H, H-21′), 0.93 (t, J = 7.3 Hz, 3H,
H-22), 0.87 (s, 9H, TBS), 0.86 (d, J = 7.3 Hz, 3H, H-23), 0.06
(s, 3H, TBS), 0.058 (s, 3H, TBS) ppm; 13C-NMR (100 MHz,
CDCl3, CDCl3 = 77.0 ppm) δ 177.9 (q, C-16), 159.1 (q, PMB),
130.7 (q, PMB), 129.4 (2× t, PMB), 113.7 (2× t, PMB), 80.2
(t, C-20), 70.7 (s, PMB), 69.8 (t, C-18), 55.2 (p, PMB), 41.3
(t, C-19), 38.4 (s, C-17), 25.8 (3× p, TBS), 22.7 (s, C-21), 18.0
(q, TBS), 10.5 (p, C-23), 8.5 (p, C-22), −4.7 (p, TBS), −4.8
(p, TBS) ppm; HRMS (ESI): m/z: calculated for C22H37O5Si:
409.2410 [M − H]−, found: 409.2417 [M − H]−.
1
[α]2D0 = +32.1 (c 2.0, CDCl3); H-NMR (400 MHz, CDCl3,
CHCl3 = 7.26 ppm) δ 7.28 (d, J = 8.6 Hz, 2H, PMB), 6.85 (d, J
= 8.6 Hz, 2H, PMB), 4.70 (dd, J = 11.0, 8.3 Hz, 1H, H-15),
4.49 (dd, J = 8.3, 6.0 Hz, 1H, H-15′), 4.44 (d, J = 10.7 Hz, 1H,
PMB), 4.41 (ddd, J = 6.9, 4.4, 2.9 Hz, 1H, H-18), 4.36 (d, J =
10.7 Hz, 1H, PMB), 4.34 (dd, J = 11.0, 6.0 Hz, 1H, H-14), 3.79
(s, 3H, PMB), 3.75 (s, 3H, CH3O), 3.23 (ddd, J = 7.1, 7.0,
4.9 Hz, 1H, H-20), 2.46 (dd, J = 14.5, 6.9 Hz, 1H, H-17), 2.44
(dd, J = 14.5, 2.9 Hz, 1H, H-17′), 1.99 (dddd, J = 14.3, 7.1, 7.0,
This journal is © The Royal Society of Chemistry 2012
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4.4 Hz, 1H, H-19), 1.67 (dddd, J = 14.6, 14.6, 7.1, 4.1 Hz, 1H,
H-21), 1.51–1.41 (m, 1H, H-21′), 0.91 (t, J = 7.5 Hz, 3H, H-22),
0.87 (d, J = 7.2 Hz, 3H, H-23), 0.84 (s, 9H, TBS), 0.02 (s, 3H,
TBS), −0.00 (s, 3H, TBS) ppm; 13C-NMR (100 MHz, CDCl3,
CDCl3 = 77.0 ppm) δ 171.6 (q, C-16), 169.2 (q, C-2), 159.0 (q,
PMB), 131.1 (q, PMB), 129.2 (2× t, PMB), 113.7 (2× t, PMB),
80.5 (t, C-20), 70.7 (s, PMB), 69.9 (t, C-18), 68.9 (t, C-14), 68.2
(s, C-15), 55.2 (p, PMB), 52.5 (p, CH3O), 41.4 (t, C-19), 32.2
(s, C-17), 25.7 (3× p, TBS), 22.9 (s, C-21), 17.9 (q, TBS), 10.1
(p, C-22), 8.7 (p, C-22), −4.6 (p, TBS), −4.9 (p, TBS) ppm;
HRMS (ESI): m/z: calculated for C26H44NO6Si: 494.2938
[M + H]+, found: 494.2932 [M + H]+.
room temperature overnight. After extraction with CH2Cl2, the
combined organic extracts were dried over MgSO4 and concen-
trated under reduced pressure. Purification by flash chromato-
graphy (petroleum ether–ethyl acetate = 6 : 1 → 1 : 1) furnished
aldehyde S6 as a colorless oil (438 mg, 0.9 mmol, 94%).
1
[α]2D0 = −18.1 (c 1.0, CDCl3); H-NMR (400 MHz, CDCl3,
CHCl3 = 7.26 ppm) δ 9.91 (s, 1H, H-13), 8.15 (s, 1H, H-15),
7.29 (d, J = 8.9 Hz, 2H, PMB), 6.85 (d, J = 8.9 Hz, 2H, PMB),
4.54–4.48 (m, 1H, H-18), 4.51 (d, J = 11.1 Hz, 1H, PMB), 4.35
(d, J = 11.1 Hz, 1H, PMB), 3.79 (s, 3H, PMB), 3.26 (ddd, J =
7.2, 5.5, 4.7 Hz, 1H, H-20), 2.90–2.85 (m, 2H, H-17), 1.99
(pdddd, J = 14.3, 7.2, 7.2, 4.1 Hz, 1H, H-19), 1.78–1.66 (m,
1H, H-21), 1.57–1.48 (m, 1H, H-21′), 0.94 (t, J = 7.3 Hz, 3H,
H-22), 0.92 (d, J = 7.2 Hz, 3H, H-23), 0.78 (s, 9H, TBS), −0.01
(s, 3H, TBS), −0.23 (s, 3H, TBS) ppm; 13C-NMR (100 MHz,
CDCl3, CDCl3 = 77.0 ppm) δ 184.2 (t, C-13), 165.3 (q, PMB),
159.0 (q, C-16), 143.8 (t, C-15), 140.9 (q, C-14), 130.9 (q,
PMB), 129.2 (2× t, PMB), 113.7 (2× t, PMB), 80.4 (t, C-20),
70.8 (s, C-18), 70.7 (s, PMB), 55.2 (p, PMB), 41.4 (t, C-19),
31.9 (s, C-17), 25.6 (3× p, TBS), 22.8 (s, C-21), 17.8 (q, TBS),
10.2 (p, C-23), 8.5 (p, C-22), −4.7 (p, TBS), −5.2 (p, TBS)
ppm; HRMS (ESI): m/z: calculated for C25H40NO5Si: 462.2676
[M + H]+, found: 462.2676 [M + H]+.
Methyl-2-[(2S,3R,4R)-2-(tert-butyldimethylsilyloxy)-4-(methoxy-
benzyloxy)-3-methylhexyl]oxazol-4-carboxylate (8). To a sus-
pension of anhydrous CuBr2 (0.9 g, 4.1 mmol, 4.0 equiv.) in
CH2Cl2 (15 mL) were added HMTA (0.6 g, 4.1 mmol, 4.0
equiv.) and DBU (0.6 mL, 4.1 mmol, 4.0 equiv.). A solution of
S5 (0.5 g, 1.0 mmol, 1.0 equiv.) in CH2Cl2 (15 mL) was added
to the suspension and the reaction mixture was stirred for 2 h at
room temperature. The organic solvent was removed under
reduced pressure and ethyl acetate and a solution of sat. aq.
NH4Cl/30% NH3 (1 : 1, 100 mL) were sequentially added to the
oily residue. The aqueous layer was extracted with ethyl acetate
and the combined organic extracts were sequentially washed
with a solution of sat. aq. NH4Cl/30% NH3 (1 : 1; 3×), 10%
citric acid, sat. aq. NaHCO3 and NaCl. The organic extract were
dried over MgSO4 and concentrated under reduced pressure.
Purification by flash chromatography (petroleum ether–ethyl
acetate = 5 : 1) furnished oxazole 8 as a colorless oil (0.5 g,
1.0 mmol, quant).
2-[(2S,3R,4R)-2-(tert-Butyldimethylsilyloxy)-4-(4-methoxyben-
zyloxy)-3-methylhexyl]-4-ethynyloxazole (S7). To a solution of
S6 (438 mg, 0.9 mmol, 1.0 equiv.) in MeOH (10 mL) were
sequentially added K2CO3 (328 mg, 2.4 mmol, 2.5 equiv.) and
the Ohira–Bestmann reagent 138 (456 mg, 2.4 mmol, 1.5 equiv.)
at 0 °C. The reaction mixture was allowed to warm to room
temperature overnight and was terminated by addition of Et2O
and H2O. After extraction with Et2O, the combined organic
extracts were dried over MgSO4 and concentrated under reduced
pressure. Purification by flash chromatography (petroleum ether–
ethyl acetate = 6 : 1) furnished alkine S7 as a colorless oil
(376 mg, 0.8 mmol, 84%).
1
[α]2D4 = −18.1 (c 0.4, CDCl3); H-NMR (400 MHz, CDCl3,
CHCl3 = 7.26 ppm) δ 8.14 (s, 1H, H-15), 7.28 (d, J = 8.5 Hz,
2H, PMB), 6.85 (d, J = 8.5 Hz, 2H, PMB), 4.48 (d, J = 11.3 Hz,
1H, PMB), 4.47 (ddd, J = 8.4, 4.7, 3.8 Hz, 1H, H-18), 4.34 (d, J
= 11.3 Hz, 1H, PMB), 3.90 (s, 3H, CH3O), 3.79 (s, 3H, PMB),
3.27 (ddd, J = 7.3, 5.8, 4.2 Hz, 1H, H-20), 2.91 (dd, J = 14.7,
8.4 Hz, 1H, H-17), 2.87 (dd, J = 14.7, 4.7 Hz, 1H, H-17′), 1.98
(pdddd, J = 14.3, 7.3, 7.0, 3.8 Hz, 1H, H-19), 1.71 (pdddd, J =
14.7, 14.7, 7.3, 4.2 Hz, 1H, H-21), 1.44–1.55 (m, 1H, H-21′),
0.92 (t, J = 7.3 Hz, 3H, H-22), 0.91 (d, J = 7.0 Hz, 3H, H-23),
0.78 (s, 9H, TBS), −0.02 (s, 3H, TBS), −0.23 (s, 3H, TBS)
ppm; 13C-NMR (100 MHz, CDCl3, CDCl3 = 77.0 ppm) δ 164.6
(q, C-13), 161.8 (q, PMB), 159.0 (q, C-16), 143.6 (t, C-15),
133.2 (q, C-14), 131.0 (q, PMB), 129.2 (2× t, PMB), 113.7 (2×
t, PMB), 80.5 (t, C-20), 70.8 (s, PMB), 70.7 (t, C-18), 55.2 (p,
CH3O), 52.0 (p, PMB), 41.5 (t, C-19), 32.1 (s, C-17), 25.6 (3×
p, TBS), 22.8 (s, C-21), 17.8 (q, TBS), 10.2 (p, C-23), 8.6 (p,
C-22), −4.7 (p, TBS), −5.2 (p, TBS) ppm; HRMS (ESI): m/z:
calculated for C26H42NO6Si: 492.2781 [M + H]+, found:
492.2780 [M + H]+.
1
[α]2D3 = −11.2 (c 1.0, CDCl3); H-NMR (400 MHz, CDCl3,
CHCl3 = 7.26 ppm) δ 7.71 (s, 1H, Ar-OH), 7.28 (d, J = 8.9 Hz,
2H, PMB), 6.86 (d, J = 8.9 Hz, 2H, PMB), 4.47 (d, J = 11.3 Hz,
1H, PMB), 4.44 (ddd, J = 5.9, 5.9, 4.5 Hz, 1H, H-18), 4.35 (d, J
= 11.3 Hz, 1H, PMB), 3.79 (s, 3H, PMB), 3.26 (ddd, J = 7.3,
6.0, 4.3 Hz, 1H, H-20), 3.16 (s, 1H, H-12), 2.84–2.82 (m, 2H,
H-17), 1.98 (ddd, J = 7.3, 7.1, 4.5 Hz, 1H, H-19), 1.76–1.66 (m,
1H, H-21), 1.54–1.46 (m, 1H, H-21′), 0.93 (t, J = 8.0 Hz, 3H,
H-22), 0.91 (d, J = 7.1 Hz, 3H, H-23), 0.80 (s, 9H), −0.02 (s,
3H), −0.19 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3, CDCl3 =
77.0 ppm) δ 163.7 (q, C-16), 159.0 (q, PMB), 141.6 (t, C-15),
131.0 (q, PMB), 129.3 (2× t, PMB), 122.8 (q, C-14), 113.7 (2×
t, PMB), 80.5 (q, C-13), 80.4 (t, C-20), 74.0 (t, C-12), 70.9 (s,
C-18), 70.8 (t, PMB), 55.2 (p, PMB), 41.4 (t, C-19), 32.1 (s,
C-17), 25.7 (3× p, TBS), 22.8 (s, C-21), 17.8 (q, TBS), 10.2 (p,
C-23), 8.7 (p, C-22), −4.8 (p, TBS), −5.2 (p, TBS) ppm;
HRMS (ESI): m/z: calculated for C26H40NO4Si: 458.2727
[M + H]+, found: 458.2724 [M + H]+.
2-[(2S,3R,4R)-2-(tert-Butyldimethylsilyloxy)-4-(methoxybenzyl-
oxy)-3-methylhexyl]oxazol-4-carbaldehyde (S6). To a solution
of 8 (250 mg, 1.0 mmol, 1.0 equiv.) in CH2Cl2 (15 mL) was
added Dibal-H (1.2 mol L−1 in toluene, 3.0 mL, 3.6 mmol, 6.0
equiv.) at −78 °C within 45 min. After 30 min the reaction was
terminated by addition of methanol. A saturated aqueous sol-
ution of Rochelle’s salt was added and the mixture was stirred at
2-{(2S,3R,4R)-2-(tert-Butyldimethylsilyloxy)-4-[(4-methoxy-
benzyl)oxy]-3-methylhexyl}-4-[(E)-2-iodovinyl]oxazole (9). To a
suspension of Schwartz reagent 14 (433 mg, 1.7 mmol, 2.5
equiv.) in THF (7 mL) was added S7 (308 mg, 0.7 mmol, 1.0
8302 | Org. Biomol. Chem., 2012, 10, 8298–8307
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equiv.) in THF (7 mL) at 0 °C. After 1 h NIS (378 mg,
1.7 mmol, 2.5 equiv.) in THF (8 mL) was added at −78 °C
and the reaction mixture was stirred in the dark for 40 min.
The reaction was terminated by addition of a sat. aq. Na2S2O3
solution and the aqueous layer was extracted with Et2O.
The combined organic extracts were dried over MgSO4 and
concentrated under reduced pressure. Purification by
flash chromatography (petroleum ether–ethyl acetate = 12 : 1)
furnished vinyliodide 9 as a colorless oil (348 mg, 0.6 mmol,
88%).
1H, H-15), 7.30 (d, J = 8.9 Hz, 2H, PMB), 7.22 (d, J = 7.5 Hz,
1H, H-5), 6.85 (d, J = 8.9 Hz, 2H, PMB), 6.60 (d, J = 7.5 Hz,
1H, H-6), 6.48 (pd, J = 2.0 Hz, 2H, H-12, H-13), 4.92 (dddd,
J = 11.1, 10.0, 3.4, 3.0 Hz, 1H, H-9), 4.70 (dq, J = 9.6, 2.8 Hz,
1H, H-11), 4.50 (ddd, J = 7.0, 4.6, 4.4 Hz, 1H, H-18), 4.48 (d,
J = 11.0 Hz, 1H, PMB), 4.36 (d, J = 11.0 Hz, 1H, PMB), 3.79
(s, 3H, PMB), 3.25 (ddd, J = 7.4, 5.9, 4.0 Hz, 1H, H-20), 2.98
(dd, J = 16.4, 11.1 Hz, 1H, H-8), 2.88 (dd, J = 16.4, 3.4 Hz, 1H,
H-8′), 2.85 (dd, J = 7.0, 2.4 Hz, 1H, H-17), 2.82 (dd, J = 7.0,
4.6 Hz, 1H, H-17′), 2.64 (dd, J = 13.3, 6.1 Hz, 1H, H-24), 2.39
(dd, J = 13.3, 8.2 Hz, 1H, H-24′), 2.11 (ddd, J = 14.7, 9.6,
3.0 Hz, 1H, H-10), 1.99 (dddd, J = 14.5, 7.4, 7.1, 4.4 Hz, 1H,
H-19), 1.87 (ddd, J = 14.7, 10.9, 2.8 Hz, 1H, H-10′), 1.79–1.68
(m, 1H, H-21, H-25), 1.57–1.45 (m, 1H, H-21), 1.44–1.35 (m,
1H, H-26), 1.20–1.13 (m, 1H, H-26′), 0.94 (t, J = 7.5 Hz, 3H,
H-22), 0.91 (s, 9H, TBS), 0.89 (t, J = 7.5 Hz, 3H, H-27), 0.85
(d, J = 7.1 Hz, 3H, H-23), 0.84 (d, J = 6.5 Hz, 3H, H-28), −0.03
(s, 3H, TBS), −0.23 (s, 3H, TBS) ppm; 13C-NMR (100 MHz,
CDCl3, CDCl3 = 77.0 ppm) δ 170.2 (q, C-1), 164.0 (q, C-3),
160.5 (q, PMB), 159.0 (q, C-16), 137.8 (q, C-7), 137.2 (t, C-15),
136.7 (q, C-14), 134.9 (t, C-5), 133.4 (t, C-12), 131.0 (q, PMB),
129.3 (t, PMB), 128.8 (q, C-4), 118.4 (t, C-13), 117.0 (t, C-6),
113.6 (t, PMB), 107.7 (s, C-2), 80.5 (t, C-20), 76.5 (t, C-9), 70.8
(t, C-18), 70.79 (s, PMB), 69.9 (t, C-11), 55.2 (p, PMB), 42.0 (t,
C-19), 41.6 (s, C-10), 36.8 (s, C-24), 34.7 (t, C-25), 33.3 (s,
C-8), 32.0 (s, C-17), 29.4 (s, C-26), 25.7 (3× p, TBS), 22.9 (s,
C-21), 19.0 (t, C-28), 17.9 (q, TBS), 11.5 (p, C-27), 10.1 (p,
C-22), 8.6 (p, C-23), −4.8 (p, TBS), −5.3 (p, TBS) ppm;
HRMS (ESI): m/z: calculated for C42H62NO8Si: 736.4245
[M + H]+, found: 736.4271 [M + H]+.
[α]2D3 = −12.5 (c 1.0, CDCl3); 1H-NMR (400 MHz, C6D6,
C6H6 = 7.16 ppm) δ 7.35 (d, J = 8.8 Hz, 2H, PMB), 7.27 (dd, J
= 14.4, 0.6 Hz, 1H, H-13), 6.93 (dd, J = 14.4, 0.4 Hz, 1H,
H-12), 6.87 (d, J = 8.8 Hz, 2H, PMB), 6.74 (s, 1H, H-15), 4.73
(ddd, J = 8.7, 3.8, 3.6 Hz, 1H, H-18), 4.41 (d, J = 11.1 Hz, 1H,
PMB), 4.22 (d, J = 11.1 Hz, 1H, PMB), 3.34 (s, 3H, PMB), 3.04
(ddd, J = 7.9, 4.8, 4.3 Hz, 1H, H-20), 2.74 (dd, J = 14.6, 8.7 Hz,
1H, H-17), 2.68 (dd, J = 14.6, 3.6 Hz, 1H, H-17′), 2.12–2.01
(m, 1H, H-19), 1.59 (pdddd, J = 21.9, 7.4, 7.4, 4.3 Hz, 1H,
H-21), 1.36 (pdddd, J = 21.9, 7.4, 7.4, 4.8 Hz, 1H, H-21′), 0.94
(t, J = 7.4 Hz, 3H, H-22), 0.93 (s, 9H, TBS), 0.84 (d, J =
7.0 Hz, 3H, H-23), 0.04 (s, 3H, TBS), −0.13 (s, 3H, TBS) ppm;
13C-NMR (100 MHz, C6D6, C6H6 = 128.0 ppm) δ 164.3 (q,
PMB), 159.8 (q, C-16), 140.2 (t, C-13), 134.3 (q, C-14), 133.9
(t, C-15), 131.4 (q, PMB), 129.7 (2× t, PMB), 114.1 (2× t,
PMB), 80.4 (t, C-20), 78.3 (t, C-18), 71.4 (t, C-12), 71.1 (s,
PMB), 54.8 (p, PMB), 42.0 (t, C-19), 32.0 (s, C-17), 26.0 (3× p,
TBS), 22.9 (s, C-21), 18.2 (q, TBS), 10.1 (p, C-23), 8.3 (p,
C-22), −4.6 (p, TBS), −5.0 (q, TBS) ppm; HRMS (ESI): m/z:
calculated for C26H40NO4ISiNa: 608.1669 [M + Na]+, found:
608.1674 [M + Na]+.
11-epi-15b: [α]2D6 = +6.2 (c 1.0, CDCl3); 1H-NMR (400 MHz,
CDCl3, CHCl3 = 7.26 ppm) δ 11.17 (s, 1H, Ar-OH), 7.46 (s,
1H, H-15), 7.29 (d, J = 8.5 Hz, 2H, PMB), 7.21 (d, J = 7.5 Hz,
1H, H-5), 6.84 (d, J = 8.5 Hz, 2H, PMB), 6.59 (d, J = 7.5 Hz,
1H, H-6), 6.49 (d, J = 15.7 Hz, 1H, H-13), 6.44 (dd, J = 15.7,
5.7 Hz, 1H, H-12), 4.69 (dddd, J = 8.6, 7.5, 7.2, 3.6 Hz, 1H,
H-9), 4.63 (q, J = 5.7 Hz, 1H, H-11), 4.50 (ddd, J = 7.8, 4.6,
2.9 Hz, 1H, H-18), 4.47 (d, J = 10.9 Hz, 1H, PMB), 4.35 (d, J =
10.9 Hz, 1H, PMB), 3.78 (s, 3H, PMB), 3.25 (ddd, J = 7.9, 5.8,
4.1 Hz, 1H, H-20), 3.00 (dd, J = 16.3, 8.6 Hz, 1H, H-8), 2.91
(dd, J = 16.3, 3.6 Hz, 1H, H-8′), 2.88–2.82 (m, 2H, H-17), 2.64
(dd, J = 13.3, 6.5 Hz, 1H, H-24), 2.38 (dd, J = 13.3, 7.9 Hz, 1H,
H-24′), 2.24 (ddd, J = 14.2, 7.5, 7.2 Hz, 1H, H-10), 1.97 (ddd, J
= 14.2, 7.2, 4.5 Hz, 1H, H-10′), 2.04–1.93 (m, 1H, H-19),
1.79–1.66 (m, 1H, H-25), 1.58–1.45 (m, 1H, H-21), 1.44–1.34
(m, 1H, H-21′), 1.24–1.14 (m, 2H, H-26), 0.93 (t, J = 7.5 Hz,
3H, H-22), 0.90 (s, 9H, TBS), 0.89 (t, J = 7.5 Hz, 3H, H-27),
0.84 (d, J = 7.2 Hz, 3H, H-23), 0.83 (d, J = 6.5 Hz, 3H, H-28),
−0.04 (s, 3H, TBS), −0.24 (s, 3H, TBS) ppm; 13C-NMR
(100 MHz, CDCl3, CDCl3 = 77.0 ppm) δ 170.1 (q, C-1), 164.1
(q, C-3), 160.5 (q, PMB), 159.0 (q, C-16), 137.6 (q, C-7), 137.2
(t, C-15), 136.5 (q, C-14), 135.1 (t, C-5), 132.6 (t, C-12), 131.0
(q, PMB), 129.3 (2× t, PMB), 128.9 (q, C-4), 119.5 (t, C-13),
117.1 (t, C-6), 113.6 (3× t, PMB), 107.7 (s, C-2), 80.5 (t, C-20),
77.7 (t, C-9), 70.8 (t, C-18), 70.7 (s, PMB), 69.4 (t, C-11), 55.2
(p, PMB), 41.9 (t, C-19), 41.5 (s, C-10), 36.8 (s, C-24), 34.7 (t,
C-25), 33.0 (s, C-8), 32.0 (s, C-17), 29.7 (s, C-26), 25.7 (3× p,
TBS), 22.9 (s, C-21), 19.0 (t, C-28), 17.8 (q, TBS), 11.5
(p, C-27), 10.1 (p, C-22), 8.6 (p, C-23), −4.8 (p, TBS), −5.3
18-TBS-20-PMB-protected noricumazole A 15a and 11-epi-18-
TBS-20-PMB-protected noricumazole A 15b. Method A: To a
solution of t-BuLi (1.7 mol L−1 in pentane, 0.8 mL, 1.4 mmol,
4.1 equiv.) in degassed Et2O (10 mL) was added vinyliodide 9
(388 mg, 0.7 mmol, 2.0 equiv.) in Et2O (8 mL) at −78 °C under
an argon atmosphere. After 1 h, dimethylzinc (1.2 mol L−1 in
toluene, 0.6 mL, 0.7 mmol, 2.0 equiv.) was added at −78 °C and
the reaction mixture was stirred for 15 min. Aldehyde 4 (92 mg,
0.3 mmol, 1.0 equiv.) in Et2O (8 mL) was added and stirring
was continued at −78 °C for 3 h. H2O and Et2O were added and
the aqueous layer was extracted with Et2O. The combined
organic extracts were dried over MgSO4 and concentrated under
reduced pressure. Purification by flash chromatography (pet-
roleum ether–ethyl acetate = 15 : 1 → 4 : 1) furnished allylic
alcohols 15a (82 mg, 0.1 mmol, 34%) and 11-epi-15b (82 mg,
0.1 mmol, 34%) as light yellow oils.
Method B: To a solution of nitrobenzoate S8 (2 mg,
2.3 μmol, 1.0 equiv.) in THF–MeOH (2 : 1, 0.15 mL) were
added NaOH (0.5 mg, 13.6 μmol, 6.0 equiv.) and H2O (0.1 mL)
at 0 °C. The reaction mixture was stirred for 16 h. H2O was
added and the aqueous layer was extracted with CH2Cl2. The
combined organic extracts were dried (MgSO4) and concentrated
under reduced pressure. Purification by flash chromatography
(PE : EA = 6 : 1) furnished allylic alcohol 15a as a colorless oil
(2 mg, 2.0 μmol, 90%).
15a: [α]2D6 = −15.4 (c 1.0, CDCl3); 1H-NMR (400 MHz,
CDCl3, CHCl3 = 7.26 ppm) δ 11.20 (s, 1H, Ar-OH), 7.45 (s,
This journal is © The Royal Society of Chemistry 2012
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(p, TBS) ppm; HRMS (ESI): m/z: calculated for C42H62NO8Si:
chromatography (petroleum ether–ethyl acetate = 4 : 1 → 2 : 1)
furnished 16a (25 mg, 29.9 μmol, quant) as a colorless oil.
S9a: [α]2D4 = −22.4 (c 1.0, MeOH); 1H-NMR (400 MHz,
Me2CO d6, Me2CO = 2.05 ppm) δ 7.80 (s, 1H, H-15), 7.49 (d, J
= 7.8 Hz, 1H, H-5), 7.37 (d, J = 8.8 Hz, 2H, PMB), 7.19 (d, J =
7.8 Hz, 1H, H-6), 6.88 (d, J = 8.8 Hz, 2H, PMB), 6.59 (dd, J =
15.5, 0.8 Hz, 1H, H-13), 6.40 (ddd, J = 15.5, 7.2, 0.5 Hz, 1H,
H-12), 5.67 (dq, J = 7.2, 0.8 Hz, 1H, H-11), 4.68 (ddd, J = 9.2,
4.5, 3.0 Hz, 1H, H-9), 4.57–4.53 (m, 1H, H-18), 4.51 (d, J =
11.0 Hz, 1H, PMB), 4.39 (d, J = 11.0 Hz, 1H, PMB), 3.78 (s,
3H, PMB), 3.34 (ddd, J = 8.2, 5.2, 4.0 Hz, 1H, H-20), 3.12 (dd,
J = 16.1, 3.0 Hz, 1H, H-17), 3.04 (dd, J = 16.1, 10.1 Hz, 1H,
H-17′), 2.87 (dd, J = 15.0, 3.0 Hz, 1H, H-8), 2.73 (dd, J = 15.0,
9.2 Hz, 1H, H-8′), 2.58 (dd, J = 13.3, 5.9 Hz, 1H, H-24), 2.33
(dd, J = 13.3, 8.7 Hz, 1H, H-24′), 2.32–2.27 (m, 1H, H-10),
2.29 (s, 3H, Ac), 2.10 (ddd, J = 13.9, 7.2, 4.5 Hz, 1H, H-10′),
2.06 (s, 3H, Ac), 1.98 (ddd, J = 6.6, 4.0, 1.9 Hz, 1H, H-19),
1.82 (pdddd, J = 14.6, 7.3, 7.3, 4.3 Hz, 1H, H-21), 1.69–1.59
(m, 1H, H-25), 1.50 (pdddd, J = 14.6, 7.3, 7.3, 5.2 Hz, 1H,
H-21′), 1.41–1.32 (m, 1H, H-26), 1.26–1.14 (m, 1H, H-26′),
0.93 (d, J = 6.6 Hz, 3H, H-23), 0.91 (t, J = 7.3 Hz, 3H, H-22),
0.90 (t, J = 7.4 Hz, 3H, H-27), 0.83 (d, J = 6.7 Hz, 3H, H-28),
0.75 (s, 9H, TBS), −0.03 (s, 3H, TBS), −0.25 (s, 3H, TBS)
ppm; 13C-NMR (100 MHz, Me2CO d6, Me2CO = 29.84 ppm) δ
170.3 (2× q, Ac), 169.5 (q, C-1), 164.5 (q, C-16), 160.1 (q,
PMB), 150.9 (q, C-3), 140.1 (q, C-7), 139.1 (q, C-14), 136.8 (t,
C-15), 136.7 (t, C-5), 135.3 (q, C-4), 132.1 (q, PMB), 130.2 (2×
t, PMB), 129.5 (t, C-12), 125.6 (t, C-6), 121.8 (t, C-13), 118.6
(q, C-2), 114.4 (2× t, PMB), 81.1 (t, C-20), 75.3 (t, C-18), 71.9
(t, C-9), 71.5 (s, PMB), 70.7 (t, C-11), 55.5 (p, PMB), 42.5 (t,
C-19), 40.4 (s, C-10), 37.7 (s, C-24), 36.3 (t, C-25), 34.1 (s,
C-17), 32.2 (s, C-8), under Me2CO-Signal (s, C-26), 26.2 (3× p,
TBS), 23.4 (s, C-21), 21.1 (p, Ac), 21.07 (p, Ac), 19.3 (t, C-28),
18.5 (q, TBS), 11.8 (p, C-27), 10.2 (p, C-23), 8.5 (p, C-22),
−4.5 (p, TBS), −4.9 (p, TBS) ppm; HRMS (ESI): m/z: calcu-
lated for C46H66NO10Si: 820.4456 [M + H]+, found: 820.4437
[M + H]+.
736.4245 [M + H]+, found: 736.4271 [M + H]+.
4-Nitrobenzoate S8. To a solution of 11-epi-15a (5 mg,
6.8 μmol, 1.0 equiv.) in THF (2 mL) were sequentially added tri-
phenylphosphine (18 mg, 0.1 mmol, 10.0 equiv.), 4-nitrobenzoic
acid (11 mg, 0.1 mmol, 10.0 equiv.) and diethyl azodicarboxy-
late (40% in toluene, 32 μL, 0.1 mmol, 10.0 equiv.) at 0 °C. The
reaction temperature was raised to room temperature and the
reaction stirred for 30 min. H2O was added and the aqueous
layer was extracted with ethyl acetate. The combined organic
extracts were dried over MgSO4 and concentrated under reduced
pressure. Purification by flash chromatography (petroleum ether :
ethyl acetate = 6 : 1 → 4 : 1) furnished nitrobenzoate S8 as a
colorless oil (5 mg, 5.9 μmol, 86%).
1
[α]2D1 = +12.7 (c 0.5, MeOH); H-NMR (500 MHz, Me2CO
d6, Me2CO = 2.05 ppm) δ 11.41 (s, 1H, Ar-OH), 8.39 (d, J =
8.9 Hz, 2H, CO2CCH), 8.28 (d, J = 8.9 Hz, 2H, NO2CCH), 7.34
(d, J = 7.6 Hz, 1H, H-5), 7.31 (d, J = 8.6 Hz, 2H, PMB), 7.24
(s, 1H, H-15), 6.96 (dd, J = 15.4, 10.8 Hz, 1H, H-12), 6.84 (d, J
= 8.6 Hz, 2H, PMB), 6.75 (d, J = 7.6 Hz, 1H, H-6), 6.22 (d, J =
10.8 Hz, 1H, H-13), 5.97 (ddd, J = 15.4, 11.7, 7.4 Hz, 1H,
H-11), 4.78 (dddd, J = 9.9, 5.7, 5.7, 5.6 Hz, 1H, H-9), 4.71
(ddd, J = 9.2, 6.1, 2.8 Hz, 1H, H-18), 4.47 (d, J = 11.2 Hz, 1H,
PMB), 4.35 (d, J = 11.2, 1H, PMB), 3.72 (s, 3H, PMB), 3.33
(ddd, J = 11.8, 8.5, 4.5 Hz, 1H, H-20), 3.06–3.01 (m, 2H, H-8),
2.76–2.68 (m, 2H, H-10), 2.75 (dd, J = 14.6, 6.1 Hz, 1H, H-17),
2.64 (dd, J = 13.2, 6.2 Hz, 1H, H-24), 2.54 (dd, J = 14.6,
9.2 Hz, 1H, H-17′), 2.39 (dd, J = 13.2, 8.1 Hz, 1H, H-24′),
2.09–2.01 (m, 1H, H-19), 1.86–1.77 (m, 1H, H-21), 1.77–1.69
(m, 1H, H-25), 1.54–1.44 (m, 1H, H-21′), 1.43–1.35 (m, 1H,
H-26), 1.22–1.25 (m, 1H, H-26′), 0.92 (s, 9H, TBS), 0.91 (d, J =
7.6 Hz, 3H, H-23), 0.89 (t, J = 7.1 Hz, 3H, H-27), 0.88 (t, J =
8.0 Hz, 3H, H-28), 0.85 (s, 3H, H-22), 0.07 (s, 3H, TBS), 0.05
(s, 3H, TBS) ppm; 13C-NMR (125 MHz, Me2CO d6, Me2CO =
29.84 ppm) δ 171.3 (q, C-1), 164.4 (q, C-16), 161.1 (q,
CO2CCH), 160.0 (q, C-3), 152.0 (q, NO2C), 147.5 (q, PMB),
138.4 (q, C-7), 138.1 (t, C-5), 135.3 (q, CO2CCH), 132.0 (2× t,
CO2CCH), 130.4 (t, C-11), 130.2 (2× t, PMB), 130.2 (t, C-12),
130.0 (q, C-14), 128.8 (q, C-4), 124.7 (2× t, NO2CCH), 119.3
(t, C-13), 118.3 (t, C-6), 114.3 (2× t, PMB), 108.8 (q, C-2), 96.2
(t, C-15), 80.6 (t, C-20), 80.0 (t, C-9), 71.3 (s, PMB), 70.6
(t, C-18), 55.4 (p, PMB), 42.3 (t, C-19), 38.8 (s, C-10), 37.2
(s, C-24), 35.6 (t, C-25), 32.9 (s, C-8), 32.7 (s, C-17), 29.2
(s, C-26), 26.2 (3× p, TBS), 23.1 (s, C-21), 19.2 (q, TBS), 18.6
(p, C-27), 11.7 (p, C-22), 10.1 (p, C-28), 8.3 (p, C-23), −4.37
(p, TBS), −4.4 (p, TBS) ppm; HRMS (ESI): m/z: calculated
for C49H65N2O11Si: 885.4358 [M + H]+, found: 885.4360
[M + H]+.
11-epi-S9b: yield: quant., 0.1 mmol; [α]2D5 = −12.6 (c 0.9,
1
MeOH); H-NMR (400 MHz, Me2CO d6, Me2CO = 2.05 ppm)
δ 7.80 (s, 1H, H-15), 7.49 (d, J = 7.8 Hz, 1H, H-5), 7.37 (d, J =
8.8 Hz, 2H, PMB), 7.19 (d, J = 7.8 Hz, 1H, H-6), 6.88 (d, J =
8.8 Hz, 2H, PMB), 6.59 (dd, J = 15.5, 0.8 Hz, 1H, H-13), 6.40
(ddd, J = 15.5, 7.2, 0.5 Hz, 1H, H-12), 5.67 (dq, J = 7.2, 0.8 Hz,
1H, H-11), 4.68 (ddd, J = 9.2, 4.5, 3.0 Hz, 1H, H-9), 4.57–4.53
(m, 1H, H-18), 4.51 (d, J = 11.0 Hz, 1H, PMB), 4.39 (d, J =
11.0 Hz, 1H, PMB), 3.78 (s, 3H, PMB), 3.34 (ddd, J = 8.2, 5.2,
4.0 Hz, 1H, H-20), 3.12 (dd, J = 16.1, 3.0 Hz, 1H, H-17), 3.04
(dd, J = 16.1, 10.1 Hz, 1H, H-17′), 2.87 (dd, J = 15.0, 3.0 Hz,
1H, H-8), 2.73 (dd, J = 15.0, 9.2 Hz, 1H, H-8′), 2.58 (dd, J =
13.3, 5.9 Hz, 1H, H-24), 2.33 (dd, J = 13.3, 8.7 Hz, 1H, H-24′),
2.32–2.27 (m, 1H, H-10), 2.29 (s, 3H, Ac), 2.10 (ddd, J = 13.9,
7.2, 4.5 Hz, 1H, H-10′), 2.06 (s, 3H, Ac), 1.98 (ddd, J = 6.6,
4.0, 1.9 Hz, 1H, H-19), 1.82 (pdddd, J = 14.6, 7.3, 7.3, 4.3 Hz,
1H, H-21), 1.69–1.59 (m, 1H, H-25), 1.50 (pdddd, J = 14.6, 7.3,
7.3, 5.2 Hz, 1H, H-21′), 1.41–1.32 (m, 1H, H-26), 1.26–1.14
(m, 1H, H-26′), 0.93 (d, J = 6.6 Hz, 3H, H-23), 0.91 (t, J =
7.3 Hz, 3H, H-22), 0.90 (t, J = 7.4 Hz, 3H, H-27), 0.83 (d, J =
6.7 Hz, 3H, H-28), 0.75 (s, 9H, TBS), −0.03 (s, 3H, TBS),
−0.25 (s, 3H, TBS) ppm; 13C-NMR (125 MHz, MeOH d4,
3,11-Acetate-18-TBS-20-PMB protected 11-epi-noricumazole
A S9a and 11-epi-S9b. To a solution of alcohol 15a (27 mg,
36.0 μmol, 1.0 equiv.) in CH2Cl2 (7 mL) were added DMAP
(0.9 mg, 7.2 μmol, 0.2 equiv.), pyridine (13 μL, 158.4 μmol, 4.4
equiv.) and acidic anhydride (8 μL, 79.2 μmol, 2.2 equiv.) at
room temperature. The reaction was terminated after 16 h by
addition of H2O and Et2O. The aqueous layer was extracted with
Et2O. The combined organic extracts were dried over MgSO4
and concentrated under reduced pressure. Purification by flash
8304 | Org. Biomol. Chem., 2012, 10, 8298–8307
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MeOH d3 = 49.0 ppm) δ 171.9 (2× q, Ac), 165.8 (2× q, C-1,
C-3), 160.7 (2× q, C-16, PMB), 140.7 (q, C-14), 139.0 (q, C-7),
137.73 (t, C-12), 137.7 (2× t, C-5, C-15), 132.1 (2× t, PMB),
130.8 (1× q, 1× s, PMB, C-4), 129.1 (t, C-15), 126.1 (q, C-2),
123.0 (2× t, C-6, C-13), 114.7 (2× t, PMB), 81.6 (t, C-20), 77.1
(t, C-18), 72.6 (t, C-9), 72.1 (t, C-11), 71.9 (s, PMB), 55.7 (p,
PMB), 42.8 (t, C-19), 40.2 (s, C-10), 38.1 (s, C-24), 36.8 (t,
C-25), 34.3 (s, C-8), 32.2 (s, C-17), 30.5 (s, C-26), 26.2 (3× p,
TBS), 23.6 (s, C-21), 21.14 (p, Ac), 21.1 (p, Ac), 19.4 (t, C-28),
18.7 (q, TBS), 11.9 (p, C-27), 10.1 (p, C-22), 8.4 (p, C-23),
−4.4 (p, TBS), −5.0 (p, TBS) ppm; HRMS (ESI): m/z: calcu-
lated for C46H66NO10Si: 820.4456 [M + H]+, found: 820.4437
[M + H]+.
11-epi-16b: yield: 61%, 16.7 μmol; [α]2D5 = −12.6 (c 0.9,
MeOH); 1H-NMR (500 MHz, MeOH d4, MeOH d3 = 3.31 ppm)
δ 7.79 (s, 1H, H-15), 7.48 (d, J = 7.8 Hz, 1H, H-5), 7.27 (d, J =
8.7 Hz, 2H, PMB), 7.19 (d, J = 7.8 Hz, 1H, H-6), 6.85 (d, J =
8.7 Hz, 2H, PMB), 6.56 (d, J = 15.7 Hz, 1H, H-13), 6.32 (dd, J
= 15.7, 7.2 Hz, 1H, H-12), 5.66 (ddd, J = 7.2, 7.0, 6.7 Hz, 1H,
H-11), 4.57 (ddd, J = 14.9, 8.1, 3.9 Hz, 1H, H-9), 4.42 (d, J =
11.0 Hz, 1H, PMB), 4.39 (d, J = 11.0 Hz, 1H, PMB), 4.15 (ddd,
J = 9.5, 6.6, 3.2 Hz, 1H, H-18), 3.76 (s, 3H, PMB), 3.48 (ddd, J
= 6.6, 6.1, 3.4 Hz, 1H, H-20), 3.08 (dd, J = 16.1, 3.9 Hz, 1H,
H-8), 3.00 (dd, J = 16.1, 8.1 Hz, 1H, H-8′), 2.92 (dd, J = 15.1,
3.2 Hz, 1H, H-17), 2.76 (dd, J = 15.1, 9.5 Hz, 1H, H-17′), 2.58
(dd, J = 13.4, 6.4 Hz, 1H, H-24), 2.37–2.30 (m, 1H, H-24′),
2.31 (s, 3H, Ac), 2.28 (ddd, J = 14.3, 8.1, 6.7 Hz, 1H, H-10),
2.07 (s, 3H, Ac), 2.02 (ddd, J = 14.3, 7.0, 3.9 Hz, 1H, H-10′),
2.01 (sext, J = 6.6 Hz, 1H, H-19), 1.68 (pdddd, J = 14.0, 7.5,
7.5, 3.4 Hz, 1H, H-21), 1.61 (oct, J = 6.4 Hz, 1H, H-25), 1.45
(sext, J = 7.3 Hz, 1H, H-26), 1.36 (pddd, J = 14.0, 7.5, 6.1 Hz,
1H, H-21′), 1.24–1.14 (m, 1H, H-26′), 0.93 (t, J = 7.3 Hz, 3H,
H-27), 0.91 (t, J = 7.5 Hz, 3H, H-22), 0.90 (d, J = 6.6 Hz, 3H,
H-23), 0.84 (d, J = 6.4 Hz, 3H, H-28) ppm; 13C-NMR
(125 MHz, MeOH d4, MeOH d3 = 49.0 ppm) δ 172.0 (2× q,
Ac), 171.1 (q, C-1), 165.7 (q, C-16), 160.8 (q, PMB), 150.0 (q,
C-3), 140.1 (q, C-14), 138.9 (t, C-15), 137.9 (t, C-15), 137.8 (q,
C-7), 136.0 (q, C-4), 132.0 (q, PMB), 130.8 (2× t, PMB), 129.2
(t, C-12), 126.1 (t, C-6), 122.8 (t, C-13), 118.4 (q, C-2), 114.6
(2× t, PMB), 82.0 (t, C-20), 77.2 (t, C-9), 72.5 (t, C-11), 71.9 (s,
PMB), 71.5 (t, C-18), 55.6 (p, PMB), 42.1 (t, C-19), 40.2 (s,
C-10), 38.1 (s, C-24), 36.9 (t, C-25), 34.2 (s, C-8), 33.7 (s,
C-17), 30.5 (s, C-26), 23.1 (s, C-21), 21.14 (p, Ac), 21.1 (p,
Ac), 19.4 (t, C-28), 11.9 (p, C-27), 10.7 (p, C-22), 9.6 (p, C-23)
ppm; HRMS (ESI): m/z: calculated for C40H52NO10: 706.3591
[M + H]+, found: 706.3591 [M + H]+.
3,11-Acetate-PMB protected noricumazole A 16a and 11-epi-
16b. To a solution of protected noricumazole A S9a (14 mg,
17.3 μmol, 1.0 equiv.) in THF (7 mL) was added hydrofluoric
acid in pyridine (70%, as HF 30%, 0.7 mL) via a syringe pump
over 14 h at room temperature. The reaction was terminated by
addition of sat. aq. NaHCO3 solution and the aqueous layer was
extracted with ethyl acetate. The combined organic extracts were
dried over MgSO4 and concentrated under reduced pressure. The
residue was taken up in MeOH and H2O (1 : 1) and purified by
RP-HPLC (MeOH–H2O, gradient elution). Compound 16a
(8 mg, 11.9 μmol, 69%, 89% b.r.s.m.) was obtained as a color-
less oil. As a side product acetate-protected 17a was obtained.
16a: [α]2D0 = −27.1 (c 0.8, MeOH); 1H-NMR (500 MHz,
MeOH d4, MeOH d3 = 3.31 ppm) δ 7.78 (s, 1H, H-15), 7.49 (d,
J = 7.9 Hz, 1H, H-5), 7.28 (d, J = 8.9 Hz, 2H, PMB), 7.19 (d, J
= 7.9 Hz, 1H, H-6), 6.86 (d, J = 8.9 Hz, 2H, PMB), 6.54 (dd, J
= 15.6, 0.3 Hz, 1H, H-13), 6.33 (dd, J = 15.6, 6.7 Hz, 1H,
H-12), 5.65 (dq, J = 6.7, 0.5 Hz, 1H, H-11), 4.64 (dddd, J =
10.4, 5.8, 5.8, 4.2 Hz, 1H, H-9), 4.43 (d, J = 11.3 Hz, 1H,
PMB), 4.40 (d, J = 11.3 Hz, 1H, PMB), 4.17 (ddd, J = 9.4, 6.6,
3.2 Hz, 1H, H-18), 3.77 (s, 3H, PMB), 3.49 (ddd, J = 7.2, 6.6,
3.6 Hz, 1H, H-20), 3.05 (dd, J = 14.6, 4.2 Hz, 1H, H-8), 3.01
(dd, J = 16.6, 10.4 Hz, 1H, H-8′), 2.94 (dd, J = 15.2, 3.2 Hz,
1H, H-17), 2.77 (dd, J = 15.2, 9.4 Hz, 1H, H-17′), 2.59 (dd, J =
13.3, 6.1 Hz, 1H, H-24), 2.38–2.31 (m, 1H, H-24′), 2.31 (s, 3H,
Ac), 2.14 (dd, J = 6.7, 5.8 Hz, 2H, H-10), 2.06 (s, 3H, Ac), 2.02
(sext, J = 6.6 Hz, 1H, H-19), 1.70 (pdddd, J = 7.2, 7.2, 6.6,
3.6 Hz, 1H, H-21), 1.64–1.58 (m, 1H, H-25), 1.47 (sext, J =
7.2 Hz, 1H, H-21′), 1.41–1.30 (m, 1H, H-26), 1.30–1.17 (m, 1H,
H-26′), 0.94 (t, J = 7.2 Hz, 3H, H-27), 0.91 (t, J = 8.7 Hz, 3H,
H-22), 0.90 (d, J = 7.9 Hz, 3H, H-23), 0.85 (d, J = 6.6 Hz, 3H,
3,11-Diacetyl protected noricumazole A 17a and 11-epi-
17b. 17a: yield: 6%, 1.0 μmol; [α]2D4 = −12.5 (c 0.9, MeOH);
1H-NMR (500 MHz, MeOH d4, MeOH d3 = 3.31 ppm) δ 7.79
(s, 1H, H-15), 7.49 (d, J = 7.8 Hz, 1H, H-5), 7.21 (d, J = 7.8 Hz,
1H, H-6), 6.54 (dd, J = 15.8, 0.6 Hz, 1H, H-13), 6.32 (dd, J =
15.8, 6.5 Hz, 1H, H-12), 5.65 (q, J = 6.5 Hz, 1H, H-11),
4.69–4.63 (m, 1H, H-9), 4.18 (ddd, J = 9.5, 6.7, 3.3 Hz, 1H,
H-18), 3.54 (ddd, J = 9.0, 6.7, 2.6 Hz, 1H, H-20), 3.09–3.05 (m,
1H, H-8), 3.00 (dd, J = 16.4, 3.9 Hz, 1H, H-8′), 3.00 (dd, J =
15.1, 3.3 Hz, 1H, H-17), 2.81 (dd, J = 15.1, 9.5 Hz, 1H, H-17′),
2.59 (dd, J = 13.4, 6.1 Hz, 1H, H-24), 2.41–2.32 (m, 1H,
H-24′), 2.32 (s, 3H, Ac), 2.15 (pt, J = 6.5 Hz, 2H, H-10), 2.07
(s, 3H, Ac), 1.77 (sext, J = 6.7 Hz, 1H, H-19), 1.69–1.58 (m,
2H, H-21, H-25), 1.45–1.33 (m, 2H, H-21′, H-26), 1.25–1.17
(sext, J = 7.2 Hz, 1H, H-26′), 0.98 (t, J = 7.4 Hz, 3H, H-27),
0.92 (t, J = 7.5 Hz, 3H, H-22), 0.91 (d, J = 7.0 Hz, 3H, H-23),
0.85 (d, J = 6.6 Hz, 3H, H-28) ppm; 13C-NMR (125 MHz,
MeOH d4, MeOH d3 = 49.0 ppm) δ 172.1 (2× q, Ac), 171.2 (q,
C-1), 165.9 (q, C-16), 149.6 (q, C-3), 140.7 (q, C-7), 138.9 (t,
C-5), 137.8 (t, C-15), 130.7 (q, C-14), 129.8 (t, C-12), 126.1 (t,
C-6), 122.0 (t, C-13), 118.5 (q, C-4), 114.8 (q, C-2), 76.3 (t,
C-9), 75.4 (t, C-20), 72.3 (t, C-18), 71.6 (t, C-11), 45.6 (t, C-19),
40.5 (s, C-10), 38.1 (s, C-24), 36.9 (t, C-25), 34.3 (s, C-8), 33.7
(s, C-17), 30.5 (s, C-26), 27.2 (s, C-21), 21.1 (p, Ac), 21.0
(p, Ac), 19.4 (t, C-28), 11.9 (p, C-23), 11.3 (p, C-22), 10.4
H-28) ppm; 13C-NMR (125 MHz, MeOH d4, MeOH d3
=
49.0 ppm) δ 172.1 (2× q, Ac), 171.2 (q, C-1), 165.7 (q, C-16),
160.8 (q, PMB), 149.7 (q, C-3), 140.6 (q, C-7), 139.0 (q, C-14),
137.8 (t, C-15), 137.7 (t, C-5), 135.5 (q, C-4), 132.1 (q, PMB),
130.8 (2× t, PMB), 129.8 (t, C-12), 126.1 (t, C-6), 122.0 (t,
C-13), 118.6 (q, C-2), 114.7 (2× t, PMB), 82.1 (t, C-20), 76.3 (t,
C-9), 72.0 (s, PMB), 71.7 (t, C-11), 71.6 (t, C-18), 55.7 (p,
PMB), 42.1 (t, C-19), 40.5 (s, C-10), 38.1 (s, C-24), 36.9 (t,
C-25), 34.3 (s, C-8), 33.8 (s, C-17), 30.5 (s, C-26), 23.1 (s,
C-21), 21.1 (p, Ac), 21.0 (p, Ac), 19.4 (t, C-28), 11.9 (p, C-27),
10.8 (p, C-23), 9.6 (p, C-22) ppm; HRMS (ESI): m/z: calculated
for C40H52NO10: 706.3591 [M
+
H]+, found: 706.3591
[M + H]+.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8298–8307 | 8305

View Article Online
(p, C-27) ppm; HRMS (ESI): m/z: calculated for C32H44NO9:
586.3016 [M + H]+, found: 586.3002 [M + H]+.
(dd, J = 13.5, 8.4 Hz, 1H, H-24′), 2.28–2.24 (m, 1H, H-19),
2.03 (ddd, J = 14.7, 9.0, 4.1 Hz, 1H, H-10), 1.91 (ddd, J = 14.7,
6.8, 3.5 Hz, 1H, H-10′), 1.73 (ddd, J = 14.5, 7.1, 3.7 Hz, 1H,
H-21), 1.63–1.55 (m, 1H, H-25), 1.46–1.37 (m, 1H, H-21′), 1.45
(sext, J = 7.0 Hz, 1H, H-26), 1.18 (sext, J = 7.0 Hz, 1H, H-26′),
0.98 (t, J = 7.0 Hz, 3H, H-22), 0.91 (t, J = 7.1 Hz, 3H, H-27),
0.90 (d, J = 7.0 Hz, 3H, H-23), 0.82 (d, J = 6.6 Hz, 3H, H-28)
ppm; 13C-NMR (125 MHz, MeOH d4, MeOH d3 = 49.0 ppm) δ
172.0 (2× q, Ac), 171.2 (q, C-1), 167.6 (q, Bz), 167.1 (q, Bz),
166.5 (q, Bz), 164.7 (q, C-16), 160.7 (q, PMB), 149.0 (q, C-3),
140.6 (t, C-7), 139.1 (t, C-15), 137.8 (q, C-5), 134.9 (q, C-14),
130.91 (q, PMB), 130.9 (3× t, Bz), 130.89 (2× t, PMB), 130.8
(2× t, Bz), 129.9 (2× t, Bz), 129.86 (t, C-12), 129.8 (q, C-4),
129.77 (3× t, Bz), 128.9 (t, C-5), 127.0 (t, C-6), 121.8 (t, C-13),
118.5 (q, C-2), 114.7 (2× t, PMB), 107.4 (t, C-1′), 83.3 (t, C-4′),
83.1 (t, C-2′), 81.2 (t, C-20), 79.2 (t, C-3′), 79.1 (t, C-18), 76.1
(t, C-9), 71.6 (s, PMB), 71.4 (t, C-11), 65.0 (s, C-5′), 55.6 (p,
PMB), 40.5 (t, C-19), 40.2 (s, C-10), 38.1 (s, C-24), 36.8 (t,
C-25), 34.3 (s, C-8), 31.1 (s, C-17), 30.5 (s, C-26), 23.2 (s,
C-21), 21.1 (p, Ac), 21.0 (p, Ac), 19.4 (t, C-28), 11.9 (p, C-22),
10.9 (p, C-23), 19.7 (p, C-27) ppm; HRMS (ESI): m/z: calcu-
lated for C66H72NO17: 1150.4800 [M + H]+, found: 1150.4789
[M + H]+.
11-epi-17b: yield: 13%, 3.6 μmol; [α]2D5 = −12.6 (c 0.9,
MeOH); 1H-NMR (500 MHz, MeOH d4, MeOH d3 = 3.31 ppm)
δ 7.78 (s, 1H, H-15), 7.49 (d, J = 7.8 Hz, 1H, H-5), 7.19 (d, J =
7.8 Hz, 1H, H-6), 6.55 (dd, J = 15.6, 0.2 Hz, 1H, H-13), 6.31
(dd, J = 15.6, 7.1 Hz, 1H, H-12), 5.66 (ddd, J = 7.1, 6.9, 6.9 Hz,
1H, H-11), 4.58 (ddd, J = 7.1, 6.9, 6.9 Hz, 1H, H-9), 4.17
(dddd, J = 10.5, 8.1, 3.9, 3.6 Hz, 1H, H-18), 3.53 (ddd, J = 8.9,
6.6, 2.7 Hz, 1H, H-20), 3.06 (dd, J = 16.0, 3.6 Hz, 1H, H-8),
3.04 (dd, J = 16.0, 3.9 Hz, 1H, H-8′), 3.00 (dd, J = 15.0, 3.2 Hz,
1H, H-17), 2.80 (dd, J = 15.0, 9.6 Hz, 1H, H-17′), 2.58 (dd, J =
13.4, 6.1 Hz, 1H, H-24), 2.34–2.31 (m, 1H, H-24′), 2.31 (s, 3H,
Ac), 2.28 (ddd, J = 14.4, 8.1, 6.9 Hz, 1H, H-10), 2.11–2.06 (m,
1H, H-10′), 2.08 (s, 3H, Ac), 1.76 (sext, J = 6.6 Hz, 1H, H-19),
1.67–1.57 (m, 2H, H-21, H-25), 1.43–1.33 (m, 2H, H-21′,
H-26), 1.27–1.15 (m, 1H, H-26′), 0.97 (t, J = 7.4 Hz, 3H, H-27),
0.91 (t, J = 7.5 Hz, 3H, H-22), 0.89 (d, J = 6.6 Hz, 3H, H-23),
0.84 (d, J = 6.6 Hz, 3H, H-28) ppm; 13C-NMR (125 MHz,
MeOH d4, MeOH d3 = 49.0 ppm) δ 172.0 (2× q, Ac), 171.1 (q,
C-1), 165.9 (q, C-16), 151.9 (q, C-3), 138.8 (t, C-15), 137.9 (t,
C-5), 137.8 (q, C-7), 130.7 (q, C-14), 129.2 (2× t, C-6, C-12),
126.1 (t, C-4), 122.7 (t, C-13), 114.8 (q, C-2), 77.2 (t, C-9), 75.4
(t, C-20), 72.5 (t, C-11), 72.3 (t, C-18), 45.6 (t, C-19), 40.2 (s,
C-10), 38.1 (s, C-24), 36.9 (t, C-25), 34.7 (t, C-25), 34.2 (s,
C-8), 33.7 (s, C-17), 30.5 (s, C-26), 27.2 (s, C-21), 21.1 (p, Ac),
21.08 (p, Ac), 19.4 (t, C-28), 11.9 (p, C-23), 11.3 (p, C-22),
10.4 (p, C-27) ppm; HRMS (ESI): m/z: calculated for
C32H44NO9: 586.3016 [M + H]+, found: 586.3002 [M + H]+.
Aglycon (-PMB) S11. To a solution of aglycon S10 (3 mg,
2.9 μmol, 1.0 equiv.) in CH2Cl2 (1.5 mL) were added phosphate
buffer (0.3 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(1 mg, 5.7 μmol, 2.0 equiv.) in CH2Cl2 (0.7 mL) at room temp-
erature. After stirring for 1.5 h the reaction was quenched by
addition of a sat. aq. NaHCO3 solution and the aqueous layer
was extracted with CH2Cl2. The combined organic extracts were
dried over MgSO4 and concentrated under reduced pressure. The
residue was taken up in MeOH and H2O (1 : 1) and purified by
RP-HPLC (MeOH–H2O, gradient elution). Compound S11
(3 mg, 2.8 μmol, 98%) was obtained as a colorless oil.
Aglycon S10. A solution of acceptor 16a (8 mg, 11.9 μmol,
1.0 equiv.) in CH2Cl2 (2.3 mL) was added to activated molecular
sieves (powder, 4 Å) under an atmosphere of argon. Hg(CN)2
(7 mg, 26.1 μmol, 2.2 equiv.) was added to the suspension at
room temperature. After stirring for 45 min glycosyl donor 18
(45 mg, 85.6 μmol, 7.2 equiv.) in CH2Cl2 (1.5 mL) which was
codistilled before with benzene was added. After 2.25 h the reac-
tion was quenched by addition of MeOH. The reaction mixture
was filtered over Celite® and the organic layer washed with a
sat. aq. KBr solution and water. The organic extract was dried
over MgSO4 and concentrated under reduced pressure. The
residue was taken up in MeOH and H2O (1 : 1) and purified by
RP-HPLC (MeOH–H2O, gradient elution). Aglycon S10 (6 mg,
5.2 μmol, 47%) was obtained as a colorless oil.
1
[α]2D2 = −21.8 (c 0.3, MeOH); H-NMR (500 MHz, MeOH
d4, MeOH d3 = 3.31 ppm) δ 8.08–8.03 (m, 2H, Bz), 7.98–7.92
(m, 4H, Bz), 7.70 (s, 1H, H-15), 7.68–7.63 (m, 2H, Bz),
7.54–7.49 (m, 2H, Bz), 7.98–7.95 (m, 1H, Bz), 7.44 (d, J =
7.9 Hz, 1H, H-5), 7.30–7.25 (m, 2H, Bz), 7.16 (d, J = 7.9 Hz,
1H, H-6), 6.33 (d, J = 15.6 Hz, 1H, H-13), 6.24 (dd, J = 15.6,
6.3 Hz, 1H, H-12), 5.55–5.48 (m, 1H, H-11), 5.45 (pdd, J = 4.6,
1.2 Hz, 1H, H-4′), 5.35 (ps, 1H, H-2′), 5.15 (ps, 1H, H-1′), 4.74
(dd, J = 11.7, 4.6 Hz, 1H, H-5′), 4.63 (dd, J = 11.7, 4.6 Hz, 1H,
H-5′′), 4.57 (dd, J = 9.2, 4.6 Hz, 1H, H-3′), 4.55–4.59 (m, 2H,
H-9, H-18), 3.50–3.47 (m, 1H, H-20), 3.09–2.99 (m, 2H, H-8),
2.97 (dd, J = 16.6, 3.9 Hz, 1H, H-17), 2.92 (dd, J = 16.6,
10.6 Hz, 1H, H-17′), 2.57 (dd, J = 13.5, 6.3 Hz, 1H, H-24),
2.36–2.31 (m, 1H, H-24′), 2.31 (s, 3H, Ac), 2.14–2.09 (m, 1H,
H-19), 2.03–1.94 (m, 2H, H-10), 2.00 (s, 3H, Ac), 1.69–1.63
(m, 1H, H-21), 1.62–1.54 (m, 1H, H-25), 1.46–1.39 (m, 1H,
H-21′), 1.31–1.25 (m, 1H, H-26), 1.19–1.13 (m, 1H, H-26′),
1.03 (d, J = 6.8 Hz, 3H, H-23), 1.00 (t, J = 7.3 Hz, 3H, H-22),
0.92 (t, J = 7.3 Hz, 3H, H-27), 0.83 (d, J = 6.5 Hz, 3H, H-28)
ppm; 13C-NMR (125 MHz, MeOH d4, MeOH d3 = 49.0 ppm) δ
172.0 (2× q, Ac), 171.2 (q, C-1), 167.6 (q, Bz), 167.1 (q, Bz),
166.5 (q, Bz), 165.1 (q, C-16), 150.0 (q, C-3), 140.6 (q, C-14),
139.0 (q, C-7), 137.8 (t, C-5), 134.8 (t, C-12), 134.4 (t, C-15),
130.9 (6× t, Bz), 130.6 (4× t, Bz), 129.9 (2× t, Bz), 129.8 (2× t,
1
[α]2D2 = −10.3 (c 0.5, MeOH); H-NMR (500 MHz, MeOH
d4, MeOH d3 = 3.31 ppm) δ 8.08–8.02 (m, 2 H, Bz), 7.98–7.91
(m, 4 H, Bz), 7.69 (s, 1H, H-15), 7.67–7.59 (m, 2H, Bz),
7.46–7.45 (m, 5H, Bz), 7.44 (d, J = 7.8 Hz, 1H, H-5), 7.28–7.20
(m, 2H, Bz), 7.19 (d, J = 8.7 Hz, 2H, PMB), 7.15 (d, J = 7.8 Hz,
1H, H-6), 6.78 (d, J = 8.7 Hz, 2H, PMB), 6.32 (d, J = 15.8 Hz,
1H, H-13), 6.26 (dd, J = 15.8, 6.4 Hz, 1H, H-12), 5.60–5.50 (m,
1H, H-11), 5.41 (pd, J = 4.7 Hz, 1H, H-4′), 5.39 (ps, 1H, H-2′),
5.17 (ps, 1H, H-1′), 4.69 (dd, J = 11.9, 3.4 Hz, 1H, H-5′), 4.61
(d, J = 11.1 Hz, 1H, PMB), 4.59 (dd, J = 11.9, 5.1 Hz, 1H,
H-5′′), 4.58–4.56 (m, 1H, H-9), 4.47 (d, J = 11.1 Hz, 1H, PMB),
4.48 (dd, J = 8.3, 4.7 Hz, 1H, H-3′), 4.41–4.36 (m, 1H, H-18),
3.71 (s, 3H, PMB), 3.47–3.42 (m, 1H, H-20), 3.00 (dd, J = 15.8,
4.0 Hz, 1H, H-17), 2.98–2.93 (m, 2H, H-8), 2.89 (dd, J = 15.8,
10.8 Hz, 1H, H-17′), 2.56 (dd, J = 13.5, 6.1 Hz, 1H, H-24), 2.29
8306 | Org. Biomol. Chem., 2012, 10, 8298–8307
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found: 634.3228 [M + H]+. For NMR-spectra and data see Fig. 2
and refer to ref. 1.
Acknowledgements
We are grateful to the Ministerium für Wissenschaft und Kultur
(MWK) in Niedersachsen for supporting J. B. We thank Prof.
Rolf Müller (Universität Saarbrücken, Germany) for helpful
advice during manuscript preparation.
Notes and references
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S. Benson, J. Wegner and A. Kirschning, Angew. Chem., 2012, 124,
1282–1286, (Angew. Chem., Int. Ed., 2012, 51, 1256–1260).
2 J. Barbier, J. Wegner, S. Benson, T. Pietschmann, J. Gentzsch and
A. Kirschning, Chem.–Eur. J., 2012, 18, 9083–9090.
3 (a) S. Ek, H. Kartimo, S. Mattila and A. Tolonen, J. Agric. Food Chem.,
2006, 54, 9834–9842; (b) R. C. Beier and B. P. Mundy, J. Carbohydr.
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Fig. 2 1H-NMR spectra of authentic (blue; bottom) and synthetic (red;
top) noricumazole B (1b).
4 Recently a new method for assigning the configuration of five-membered
Bz), 129.6 (4× t, Bz), 127.1 (q, C-2), 126.1 (t, C-6), 121.8 (t,
C-13), 118.6 (q, C-4), 107.7 (t, C-1′), 83.4 (t, C-2′), 82.9 (t,
C-3′), 79.2 (t, C-4′), 79.1 (t, C-18), 76.2 (t, C-9), 74.9 (t, C-20),
71.4 (t, C-11), 64.9 (s, C-5′), 44.4 (t, C-19), 40.2 (s, C-10), 38.1
(s, C-24), 36.8 (t, C-25), 34.2 (s, C-17), 30.5 (s, C-26), 30.4 (s,
C-8), 27.8 (s, C-21), 21.0 (2× p, Ac), 19.4 (t, C-28), 11.9 (p,
C-23), 11.0 (p, C-22), 10.5 (p, C-27) ppm; HRMS (ESI): m/z:
calculated for C58H64NO16: 1030.4225 [M + H]+, found:
1030.4240 [M + H]+.
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Noricumazole B (1b). A solution of aglycon S11 (2 mg,
1.5 μmol, 1.0 equiv.) in MeOH–THF–H2O–Et3N (1.4 mL,
6 : 5 : 1 : 2) was stirred at 55 °C. After stirring for 2 days the
solvent of the reaction mixture was removed and the residue
directly taken up in MeOH and H2O (1 : 1) and purified by
RP-HPLC (MeOH–H2O, gradient elution). Noricumazole B (1b)
(1 mg, 1.4 μmol, 98%) was obtained as a colorless oil.
Synthetic noricumazole B: [α]2D2 = +14.8 (c 0.1, MeOH); auth-
entic noricumazole B1: [α]2D0 = +13.3 (c 0.86 in MeOH); HRMS
(ESI): m/z: calculated for C33H48NO11: 634.3227 [M + H]+,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8298–8307 | 8307