Stereocontrolled synthesis of the tetracyclic core framework of (-)-lemonomycin

Article abstract of DOI:10.1055/s-2008-1078273

In a convergent approach, an advanced intermediate (2) in a projected total synthesis of the alkaloid (-)-lemonomycin (1) was prepared from readily available starting materials. The key transformations were a Pictet-Spengler cyclization, a Strecker-type amino alkylation, and an N-acyliminium cyclization. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078273

LETTER
2443
Stereocontrolled Synthesis of the Tetracyclic Core Framework of
(–)-Lemonomycin
S
tereocontroll
e
t
s
of the
e
Tetracycli
r
c
Core Framew
S
or
k
of (–)-Le
m
onom
e
ycin ngalewicz, Lothar Brecker, Johann Mulzer*
Institute of Organic Chemistry, University of Vienna, Währingerstraße 38, 1090 Vienna, Austria
Fax +43(1)42779521; E-mail: johann.mulzer@univie.ac.at
Received 4 June 2008
plex bridged tetracyclic core, a surprisingly stable hydrate
functionality and an unstable hemiaminal moiety
(Scheme 1).
Abstract: In a convergent approach, an advanced intermediate (2)
in a projected total synthesis of the alkaloid (–)-lemonomycin (1)
was prepared from readily available starting materials. The key
transformations were a Pictet–Spengler cyclization, a Strecker-type
amino alkylation, and an N-acyliminium cyclization.
No wonder that 1 has attracted the attention of the synthet-
ic community for quite a while, and indeed, several ap-
proaches to lemonomycin derivatives and intermediates
have been reported.4 However, only one total synthesis of
the natural product was completed thus far by Stoltz et al.
in 2003.5 Our retrosynthetic analysis of 1 leads back to
key intermediate 2, which contains the entire core frag-
ment of the molecule. Removal of the benzylic hydroxy
function, attachment of the amino sugar and elaboration
of the hydrate functionality, as well as the labile quinone
and hemiaminal moieties should be carried out at a late
stage of the synthesis. Herein, we report a stereocontrolled
access to enantiomerically enriched tetracycle 2 via tet-
rahydroisoquinoline 3, which in turn is assembled from
readily available starting materials 4,6 5, and 6.7 As illus-
trated in Scheme 2, the synthesis of 3 was started by con-
Key words: lemonomycin, antitumor antibiotic, tetrahydroisoquin-
oline, acyliminium cyclization, Pictet–Spengler reaction
(–)-Lemonomycin (1), a tetrahydroisoquinoline antitumor
antibiotic,1 was first isolated from a fermentation broth of
Streptomyces candidus (LL-AP191) in 1964.2 The com-
pound was found to exhibit potent antibiotic activity
against Staphylococcus aureus, Bacillus subtilis, and En-
terococcus faecium, for example, as well as high cytotoxic
properties against a human colon cancer cell line (HCT-
116). Despite its early isolation, the structure of this com-
plex alkaloid could not be elucidated before 2000, when
this goal was finally achieved by He and co-workers.3
Lemonomycin (1) exhibits rare structural features such as
a unique 2,6-dideoxy-4-amino sugar attached to a com-
OBn
Me
Fmoc
Me
MeO
Me
t-BuLi, then 4
N
6
O
THF, –78 °C
64%
Me2N
Me
O
OMe OH
HO
7
Me
OBn
CN
O
N
1. PCC, CH2Cl2, r.t., 75%
2. DIBAL-H, THF, 0 °C, 85%
OAc
O
D
OH
B
MeO
Me
MeO
Me
N
C
N
NH
A
OBn
OBn
Fmoc
Fmoc
Me
Me
1. TBSCl,
MeO
Me
MeO
OMe OH
O
NH2
N
imidazole, DMF, r.t.
OH
O
HO
1
2
2. piperidine
THF, r.t.
86% (2 steps)
Me
OMe OH
OMe OTBS OH
OBn
9
8
OBn
1. TESCl, py
CH2Cl2, r.t.
2. Pd/C, H2
MeOH, r.t.
OBn
OH
O
5
MeO
Me
MeO
NH
O
Me
Me
OTES
90% (2 steps)
Br
Me
N
OBn
OBn
NH
OMe
OMe OTBS
OH
OH
Fmoc
O
MeO
Me
MeO
Me
5
O
6
4
3
NH2
AcOH
4 Å MS
Scheme 1 Structure and retrosynthetic analysis of 1
CH2Cl2, 81%
OMe OTBS OTES
OMe OTBS OTES
SYNLETT 2008, No. 16, pp 2443–2446
Advanced online publication: 22.08.2008
x
x
.x
x
.2
0
0
8
10
3
DOI: 10.1055/s-2008-1078273; Art ID: G19008ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthesis of tetrahydroisoquinoline 3

2444
P. Siengalewicz et al.
LETTER
verting bromide 6 into the organolithium derivative, to the aldehyde which was attacked in situ by the Fmoc-
which was added to aldehyde 4 to afford secondary alco- protected nitrogen to furnish tricyclic hemiaminal 15.
hol 7 as a 2.5:1 mixture of the syn and anti diastereomers. Treatment of 15 with trifluoroacetic acid in THF triggered
This mixture was subjected to an oxidation–reduction se- a cascade reaction (Scheme 4) by generating an acylimin-
quence in order to obtain the syn diastereomer 8 as the ium cation, which due to the steric repulsion from the
only product. O-TBS protection followed by simulta- neighboring OTBS group, was intercepted by the si face
neous removal of the Fmoc and acetonide protecting of the allylsilane moiety. Thus, the vinyl sidechain was di-
groups smoothly provided amino alcohol 9. Protection of rected into the desired S configuration. Subsequently, the
the primary hydroxy function as triethylsilyl ether and cyano group at C-17 was isomerized into the less hindered
deprotection of the phenol OH group8 furnished interme- equatorial position via an iminium ion intermediate and
diate 10 as a suitable substrate for the Pictet–Spengler re- the TBS group was removed (Scheme 4). The resulting
action.9 In fact, tetrahydroisoquinoline 3 was generated as tetracycle 2 contains all stereocenters with correct
a single diastereomer via slow addition of benzyloxy acet- relative14 and absolute configurations as required for the
aldehyde 5 to a mixture of 10, acetic acid and molecular synthesis of the (–)-lemonomycin aglycon.
sieves.10 Addition of cyanohydrin sidechain 1111 in tri-
fluoroethanol furnished amino nitrile 12 as the main dia-
In summary, we have developed a concise thirteen-step
synthesis of the tetracyclic lemonomycin core fragment
stereomer in acceptable yield (Scheme 3). Acetylation of
215 from simple building blocks with complete control
the free phenol OH function provided acetate 13.12 To set
over all six stereocenters. Conversion of 2 to (–)-lemono-
the stage for the closure of the piperazine ring, the primary
mycin (1) is currently under investigation in our laborato-
ries.
OTES function was deprotected with HF in pyridine to
give alcohol 14. Dess–Martin periodinane oxidation13 led
OBn
CN
OBn
CN
CN
OH
OAc
H
H
H
N
MeO
Me
N
MeO
Me
N
Ac2O, py
CH2Cl2, r.t.
HO
Fmoc
TMS
N
Fmoc
TMS
N
Fmoc
TMS
CF3CH2OH, r.t.
58%
3
+
98%
OMe OTBS OTES
OMe OTBS OTES
12
13
11
HF/py, py
THF, r.t.
88%
OBn
OBn
OAc
CN
OAc
CN
H
MeO
Me
N
MeO
DMP
TFA, THF
0 °C
N
Fmoc
TMS
17
N
CH2Cl2, r.t.
2
N
Me
Fmoc
TMS
89%
58%
OMe OTBS OH
OMe OTBS OH
14
15
Scheme 3 Synthesis of tetracyclic key intermediate 2
SiMe3
TBS
TBS
BnO
SiMe3
BnO
O
TBS
BnO
H
OMe
O
O
Me
MeO
OMe
OMe
TfOH
Me
MeO
– Me3SiOTf
Me
MeO
N
–OTf
OH
N
N
N+
AcO
AcO
N
17
AcO
N
Fmoc
Fmoc
CN
Fmoc
CN
CN
15
TBS
TBS
BnO
H
BnO
OMe
BnO
H
H
OH
+ TfOH
–TBSOTf
O
O
OMe
OMe
Me
MeO
Me
MeO
Me
MeO
N
N
N
NC
+
NC
AcO
N
AcO
AcO
N
N
Fmoc
Fmoc
Fmoc
CN–
2
Scheme 4 Cascade sequence from 15 to 2
Synlett 2008, No. 16, 2443–2446 © Thieme Stuttgart · New York

LETTER
Stereocontrolled Synthesis of the Tetracyclic Core Framework of (–)-Lemonomycin
2445
H), 5.08 (d, J = 2.2 Hz, 1 H), 4.60 (dd, J = 12.2, 13.2 Hz, 2
H), 4.42 (t, J = 5.9 Hz, 1 H), 3.85 (dd, J = 3.8, 5.4 Hz, 2 H),
3.81 (s, 3 H), 3.72 (s, 3 H), 3.61 (d, J = 4.3 Hz, 1 H), 3.24 (m,
2 H), 2.26 (s, 3 H), 0.92 (t, J = 7.9 Hz, 6 H), 0.88 (s, 9 H),
0.56 (dd, J = 4.2, 7.9 Hz, 9 H), 0.20 (s, 3 H), 0.00 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 150.5, 145.8, 142.5, 138.0,
128.3, 127.7, 127.6, 125.1, 122.5, 121.4, 73.9, 73.1, 63.7,
61.8, 61.3, 60.5, 59.4, 49.3, 25.9, 18.0, 9.7, 6.7, 4.3, 4.3,
–4.5, –5.1. HRMS (180 °C, 70 eV): m/z calcd for
Acknowledgment
The authors thank Susanne Felsinger and Peter Unteregger (Insti-
tute of Organic Chemistry, University of Vienna) for their valuable
help with NMR and mass spectra, respectively.
References and Notes
(1) For a recent review of tetrahydroisoquinoline alkaloids, see:
Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 16–69.
(2) Whaley, H. A.; Patterson, E. L.; Dann, M.; Shay, A. J.;
Porter, J. N. Antimicrob. Agents Chemother. 1964, 8, 83.
(3) He, H.; Shen, B.; Carter, G. T. Tetrahedron Lett. 2000, 41,
2067.
(4) (a) Magnus, P.; Matthews, K. S. J. Am. Chem. Soc. 2005,
127, 12476. (b) Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama,
T. Chem. Commun. 2005, 394. (c) Couturier, C.; Schlama,
T.; Zhu, J. Synlett 2006, 1691. (d) Vincent, G.; Chen, Y.;
Lane, J. W.; Williams, R. M. Heterocycles 2007, 72, 385.
(5) Ashley, E. R.; Cruz, E. G.; Stoltz, B. M. J. Am. Chem. Soc.
2003, 125, 15000.
(6) Rush, J.; Bertozzi, C. R. Org. Lett. 2006, 8, 131.
(7) Preparation of aryl bromide 6 was performed via a five-step
sequence from 2,6-dimethoxytoluene according to a method
developed recently by us.
(8) No cyclization product was obtained performing the Pictet–
Spengler reaction with the corresponding benzyl-protected
phenol.
C33H56O6NSi2: 618.3634; found: 618.3624.
Synthesis of 12: Tetrahydroisoquinoline 3 (78 mg, 0.127
mmol) and cyanohydrin 11 (55 mg, 0.127 mmol) were
dissolved in anhyd 2,2,2-trifluoroethanol (800 mL). The
reaction mixture was allowed to stir at r.t. for 24 h. The
solvent was evaporated and the crude residue was purified
by flash column chromatography (hexanes–EtOAc, 7:1) to
afford a 1.6:1 mixture of two diastereomers of 12 (29 mg,
23% less polar diastereomer, 46 mg, 35% more polar
diastereomer; 75 mg, 58%, combined yield). Rf 0.69, 0.66
(hexanes–EtOAc, 2:1); [a]D20 +34.8 (c = 0.65, CHCl3). 1H
NMR (400 MHz, CDCl3; major diastereomer): d = 7.77 (m,
2 H), 7.61 (m, 2 H), 7.41 (m, 2 H), 7.27–7.34 (m, 5 H + 2 H),
6.07 (m, 1 H), 5.43–5.59 (m, 1 H), 5.35 (m, 1 H), 5.20 (m, 1
H), 4.49–4.61 (m, 2 H), 4.30–4.46 (m, 2 H + 1 H), 4.24 (m,
1 H + 1 H), 4.08 (m, 1 H), 3.97 (m, 1 H), 3.81 (m, 3 H), 3.71
(m, 1 H), 3.70 (m, 3 H), 3.42 (m, 1 H), 2.93 (t, J = 10.6 Hz,
1 H), 2.55 (m, 1 H), 2.24 (s, 3 H), 2.21 (m, 1 H), 1.65 (m, 1
H), 1.37 (m, 1 H), 0.92 (m, 9 H), 0.85 (s, 9 H), 0.60 (m, 6 H),
0.18 (s, 3 H), –0.02 (m, 9 H), –0.08 (s, 3 H). 13C NMR (100
MHz, CDCl3, two sets of signals corresponding to two
rotamers, * denotes the minor rotamer): d = 157.7*, 155.6,
150.0, 146.1, 146.1*, 144.2*, 144.1, 143.9, 143.8*, 141.7,
141.6*, 141.3*, 141.2, 138.0, 137.9*, 131.7, 130.6, 128.4,
128.4*, 128.8*, 128.8, 127.7*, 127.7, 127.6*, 127.6, 127.0,
127.0*, 125.3, 125.2*, 123.6, 123.1, 123.1*, 122.1, 121.2*,
121.1, 120.7, 120.5*, 120.0*, 119.9, 76.9, 73.1, 73.1*, 67.1,
63.4*, 62.9, 62.1*, 61.6*, 61.4, 60.7, 60.3*, 60.1, 57.6,
57.2*, 53.2, 53.1*, 50.0*, 49.6, 47.2, 34.0, 26.0, 25.7*, 23.1,
18.7*, 18.0, 9.7, 6.8, 4.3, –1.9, –2.0, –4.9, –5.1. HRMS (100
°C, 70 eV): m/z calcd for C58H83O8N3Si3Na: 1056.5386;
found: 1056.5402.
(9) For a recent review of the Pictet–Spengler reaction, see:
Youn, S. W. Org. Prep. Proc. Int. 2006, 38, 505.
(10) Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 16796.
(11) (a) The (E)-(5-bromopent-2-enyl)trimethylsilane side chain
employed in the enantioselective Myers’ alkylation reaction
was prepared by cross-metathesis between allyl-TMS and
allyl bromide. (b) Myers, A. G.; Kung, D. W.; Zhong, B.;
Movassaghi, M.; Kwon, S. J. Am. Chem. Soc. 1999, 121,
8401. (c) Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W.
J. Org. Chem. 1999, 64, 3322.
(12) Using the unprotected phenol in this reaction sequence led to
the undesired formation of the quinone system upon
treatment with Dess–Martin periodinane.
Synthesis of 13: Acetic anhydride (13 mL, 0.134 mmol) and
pyridine (18 mL, 0.223 mmol) were sequentially added to a
solution of phenol 12 (46 mg, 0.045 mmol) in CH2Cl2 (0.7
mL) at r.t. After stirring for 16 h, sat. aq NaHCO3 solution
(20 mL) was added and the resulting solution was extracted
with CH2Cl2 (3 × 25 mL). The combined organic phases
were dried over Na2SO4 and evaporated under reduced
pressure. The residue was purified by flash column
(13) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(14) The atom connectivities of all key intermediates were
proven by through-bond correlation NMR techniques. In
particular the structure of the rigid tetracyclic core in
compound 2 was in full agreement with the NOEs and all
1H–1H coupling constants.
(15) Synthesis of Tetrahydroisoquinoline 3: Acetic acid (5 mL,
0.078 mmol) and powdered 4 Å molecular sieves were
sequentially added to a solution of amino phenol 10 (75 mg,
0.16 mmol) in CH2Cl2 (2 mL). The resulting solution was
degassed by three freeze-pump-thaw cycles. A solution of
benzyloxy acetaldehyde 5 (25 mL, 0.171 mmol, 95%) in
CH2Cl2 (1 mL) was slowly added via a syringe pump to the
degassed solution over a period of 8.5 h. After stirring for 20
h at r.t., including the time of the addition, the reaction
suspension was filtered through Whatman No. 5 filter paper
to remove the molecular sieves. Sat. aq NaHCO3 solution
(40 mL) was added to the filtrate and the resulting biphasic
solution was extracted with CH2Cl2 (4 × 50 mL). The
combined organic phases were dried over Na2SO4 and
concentrated. The residue was purified by flash column
chromatography (CH2Cl2–MeOH, 99:1, then 98:2, then 9:1)
to afford tetrahydroisoquinoline 3 as pale yellow foam (77
mg, 81% after recovery of the unreacted starting material);
Rf 0.51 (CH2Cl2–MeOH, 20:1); [a]D20 +57.5 (c = 2.35,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 7.28–7.34 (m, 5
chromatography (hexanes–EtOAc, 5:1) to furnish acetate 13
(47 g, 98%) as single product. Rf 0.69 (hexanes–EtOAc,
2:1); [a]D20 –136 (c = 0.10, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 7.77 (d, J = 7.6 Hz, 2 H), 7.60 (dd, J = 3.1, 4.3
Hz, 2 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.28–7.35 (m, 2 H + 5 H),
5.42–5.59 (m, 1 H), 5.38 (m, 1 H), 5.02–5.25 (m, 1 H), 4.58
(m, 1 H), 4.27–4.47 (m, 5 H), 4.24 (m, 1 H), 4.09 (m, 1 H),
3.95 (m, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.44 (m, 1 H + 1
H), 2.88 (m, 1 H), 2.49 (m, 1 H), 2.27 (s, 3 H), 2.23 (s, 3 H),
2.21 (m, 1 H), 1.60 (m, 1 H), 1.37 (m, 2 H), 0.93 (t, J = 7.9
Hz, 9 H), 0.87 (s, 9 H), 0.60 (dd, J = 7.9, 7.9 Hz, 6 H), 0.20
(s, 3 H), –0.01 (s, 3 H), –0.02 (s, 3 H), –0.03 (s, 6 H). 13
C
NMR (100 MHz, CDCl3, two sets of signals, * denotes the
minor rotamer): d = 168.4, 168.4*, 155.6, 154.9, 150.8,
144.1*, 143.9, 141.3, 138.3, 138.1*, 136.7, 136.6*, 131.5,
130.5*, 128.3, 128.3*, 127.9, 127.8, 127.6, 127.0, 127.0*,
125.2, 125.2*, 124.6, 124.6*, 124.1, 124.0*, 122.3, 119.9,
77.6, 72.8, 67.0, 62.9, 62.5*, 61.3, 60.6, 60.4, 57.5, 57.0*,
Synlett 2008, No. 16, 2443–2446 © Thieme Stuttgart · New York

2446
P. Siengalewicz et al.
LETTER
53.8, 53.6*, 50.3*, 49.8, 47.2, 34.0, 26.0, 23.1, 20.5, 20.4*,
18.8*, 18.0, 9.9, 6.8, 4.3, –1.8, –2.0, –4.8, –4.9. HRMS (120
°C, 70 eV): m/z calcd for C60H85O9N3Si3Na: 1098.5491;
found: 1098.5505.
(c = 1.10, CHCl3). 1H NMR (400 MHz, CDCl3): d = 7.75 (m,
2 H), 7.56 (m, 2 H), 7.28–7.44 (m, 9 H), 5.59 (m, 1 H), 5.37
(m, 1 H), 5.15 (m, 1 H), 4.86–5.05 (m, 1 H), 4.79 (m, 1 H),
4.67 (m, 1 H), 4.35–4.61 (m, 6 H), 4.30, 4.22 (m, 1 H), 3.66–
3.76 (m, 6 H), 3.43 (m, 1 H), 3.13 (m, 1 H), 2.38–2.60 (m, 2
H), 2.36, 2.32 (s, 3 H), 2.22 (m, 3 H), 1.60 (m, 2 H), 0.82,
0.79 (s, 9 H), 0.18 (m, 3 H), –0.03 (s, 3 H), –0.06 (s, 6 H),
–0.09 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 170.9,
170.8, 157.3, 157.0, 152.4, 145.6, 145.5, 143.3, 143.3,
140.3, 138.3, 133.0, 129.9, 129.8, 129.4, 129.3, 129.2,
129.2, 129.1, 127.4, 127.1, 126.9, 126.8, 124.8, 123.3,
122.1, 122.0, 118.8, 75.4, 75.3, 73.1, 72.7, 70.1, 69.2, 66.1,
63.4, 63.0, 62.6, 58.8, 57.8, 56.9, 56.8, 49.1, 31.7, 31.3, 27.8,
25.0, 22.4, 20.0, 19.8, 11.8, 11.7, 0.2, 0.1, –3.1. HRMS (110
°C, 70 eV): m/z calcd for C54H69O9N3Si2Na: 982.4470;
found: 982.4455.
Synthesis of Tetracycle 2: Hemiaminal 15 (24 mg, 0.012
mmol) was treated with a mixture of THF (500 mL) and
trifluoroacetic acid (500 mL, 0.0065 mmol) at 0 °C. The
white foam of the starting material turned pink immediately
after addition of the acidic solvent mixture. After stirring for
15 min the starting material had been completely consumed.
Upon the removal of the trifluoroacetic acid under reduced
pressure, the reaction mixture changed its color from
colorless to orange and the crude product was dried under
vacuum for another 30 min. The residue was dissolved in
CH2Cl2 and the yellow solution was purified by flash column
chromatography with gradient elution (hexanes–EtOAc, 9:1,
then 3:1) to afford compound 2 (11 mg, 58%). Rf 0.50
(hexanes–EtOAc, 2:1); [a]D20 –4.4 (c = 0.22, CHCl3). 1H
NMR (600 MHz, CDCl3): d = 7.77 (d, J = 7.2 Hz, 2 H), 7.60
(m, 2 H), 7.40 (t, J = 7.2 Hz, 2 H), 7.16–7.34 (m, 5 H), 7.07
(m, 2 H), 5.81 (m, 1 H), 5.60 (m, 1 H), 5.52 (m, 1 H), 5.07
(m, 2 H), 4.79 (m, 1 H), 4.78 (dd, J = 2.6, 6.9 Hz, 1 H), 4.61
(m, 1 H), 4.43 (m, 1 H), 4.24 (m, 2 H + 2 H + 1 H), 3.77 (m,
3 H), 3.71 (m, 1 H), 3.70 (s, 3 H), 3.01 (m, 1 H), 2.91 (m, 1
H), 2.54 (m, 1 H), 2.28 (s, 3 H), 2.21 (m, 3 H), 2.00 (m, 1 H),
OH not found. 13C NMR (125 MHz, CDCl3): d = 168.8,
150.0, 141.4, 141.3, 140.1, 136.5, 128.4, 127.9, 127.7,
127.2, 127.1, 125.3, 124.9, 122.3, 120.1, 120.0, 118.3,
116.8, 115.0, 90.4, 73.3, 70.5, 62.7, 60.9, 60.8, 54.5, 54.3,
50.8, 31.9, 20.5, 9.6. HRMS (100 °C, 70 eV): m/z calcd for
C45H45O8N3Na: 778.3104; found: 778.3098.
Synthesis of 14: Compound 13 (86 mg, 0.080 mmol) was
dissolved in a mixture of 30% HF–pyridine, (100 mL),
pyridine (400 mL) and anhyd THF (2.7 mL). The reaction
mixture was stirred at r.t. for 30 min. After total consumption
of the starting material the reaction was quenched with
buffer solution (pH 7.00, 20 mL) and extracted with CH2Cl2
(2 × 25 mL). The organic extracts were washed with brine
(40 mL), dried over Na2SO4 and evaporated under reduced
pressure. The crude product was purified by flash column
chromatography (hexanes–EtOAc, 3:1) to furnish primary
alcohol 14 (68 mg, 88%) as single product. Rf 0.43 (hexanes–
EtOAc, 2:1); [a]D20 +31.8 (c = 0.65, CHCl3). 1H NMR (400
MHz, CDCl3): d = 7.76 (d, J = 7.5 Hz, 2 H), 7.59 (m, 2 H),
7.40 (m, 2 H), 7.28–7.35 (m, 7 H), 5.49 (m, 1 H), 5.22 (m, 1
H), 5.16 (m, 1 H), 4.55 (m, 2 H), 4.32–4.43 (m, 4 H), 4.24 (t,
J = 6.8 Hz, 1 H), 4.00 (m, 1 H), 3.94 (m, 1 H), 3.74 (s, 3 H),
3.73 (s, 3 H), 3.55 (m, 1 H), 3.46 (m, 1 H), 3.11 (m, 1 H),
2.48 (m, 1 H), 2.27 (s, 3 H), 2.23 (m, 1 H + 3 H), 1.35 (m, 2
H), 0.86 (m, 9 H), 0.20 (s, 3 H), –0.02 (s, 3 H), –0.03 (s, 6
H), –0.05 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 168.5,
156.0, 154.6, 150.9, 143.9, 141.3, 138.3, 136.8, 131.9,
128.4, 127.9, 127.7, 127.4, 127.1, 125.2, 124.7, 124.5,
122.1, 120.2, 119.9, 77.8, 72.9, 67.1, 63.9, 61.7, 61.3, 61.0,
60.6, 58.0, 54.2, 49.4, 47.1, 34.1, 25.9, 23.1, 20.4, 18.0, 9.9,
–1.8, –2.0, –4.8, –5.0. HRMS (150 °C, 70 eV): m/z calcd for
C54H71O9N3Si2Na: 984.4627; found: 984.4600.
Synthesis of 15: Primary alcohol 14 (53 mg, 0.055 mmol)
was dissolved in CH2Cl2 (2 mL) and cooled to 0 °C, then
Dess–Martin periodinane (67 mg, 0.22 mmol) was added.
After stirring at 0 °C for 2 h the cooling bath was removed
and the reaction mixture was stirred at r.t. for another 30
min. Sat. Na2S2O3 (10 mL) and NaHCO3 solution (10 mL)
were added and the mixture was extracted with CH2Cl2 (20
mL). The combined organic phases were washed with brine
(20 mL), dried over Na2SO4 and evaporated under reduced
pressure. The crude product was purified by flash column
chromatography (hexanes–EtOAc, 5:1) to furnish an
epimeric mixture of the two diastereomeric carbinolamines
15 (47 mg, 89%). Rf 0.71 (hexanes–EtOAc, 2:1); [a]D20 +6.5
Synlett 2008, No. 16, 2443–2446 © Thieme Stuttgart · New York