Synthesis of the C9-C21 fragment of geldanamycin via a diastereoselective substrate-controlled hydrogenation

Article abstract of DOI:10.1055/s-0028-1083625

An Ir-catalyzed diastereoselective hydrogenation was employed to establish the stereogenic center at carbon atom C14 of a C9-C21 fragment of geldanamycin. The fragment was stereoselectively synthesized from D-mannitol in 18 steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083625

LETTER
2969
Synthesis of the C9–C21 Fragment of Geldanamycin via a Diastereoselective
Substrate-Controlled Hydrogenation
C
9–C21Fragm
o
entof
G
elda
n
n
amycin y Horneff,1 Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
Received 12 August 2008
C9 by carbonyl olefination (step I).9 Fragment 2 results
Abstract: An Ir-catalyzed diastereoselective hydrogenation was
employed to establish the stereogenic center at carbon atom C14 of
a C9–C21 fragment of geldanamycin. The fragment was stereose-
lectively synthesized from D-mannitol in 18 steps.
from this consideration as a suitable precursor with the
amino group protected by a benzyloxycarbonyl (Z) group
and the double bond serving as a protected aldehyde sur-
rogate at C9. Prompted by recent advances in ansamycin
syntheses6,12 we disclose in this communication a new ac-
cess to the C9–C21 skeleton of geldanamycin, which em-
ploys a diastereoselective substrate-controlled hydro-
genation as the key step.
Key words: ansamycins, diastereoselectivity, hydrogenation, pro-
tecting groups, quinones, stereoselective synthesis
Geldanamycin (1, Scheme 1) was the first ansamycin an-
tibiotic, which was isolated from a microorganism2 but
not from higher plants. It has received recently increased
scientific attention because it was found to be a specific
inhibitor of the heat shock protein 90 (Hsp90).3 This ac-
tivity has far reaching implications in particular relating to
cancer therapy with Hsp90 being overexpressed in many
tumor cells.4 Despite the fact that geldanamycin itself is
not a suitable drug candidate due to severe side effects,5
synthetic access to it and its analogues is highly desirable
as these compounds allow a chemical evaluation of Hsp90
binding. So far two total syntheses of geldanamycin (1)
have been reported.6 A considerable number of synthetic
analogues have been prepared either by derivatization of
the natural product7 or by de novo synthesis.8,9
The synthesis of the hydrogenation precursor 8 com-
menced with bissilyl ether 3 (TIPS = triisopropylsilyl),
which was obtained by silylation (TIPSCl, imidazole,
DMF, r.t., 4 h, 82%) from the corresponding literature-
known dimethoxytetraol, which in turn is accessible in
three steps from D-mannitol.13 Glycol cleavage was
achieved with lead(IV) acetate to yield the protected D-glyc-
eraldehyde, which was directly taken into an E-selective
Wittig reaction with easily available14 ylide 4 (dr: E/Z =
97:3). Reduction of the ester to the corresponding primary
alcohol 5 was accomplished with LAH in almost quanti-
tative yield (Scheme 2). Attempts to convert the resulting
alcohol directly into bromide 6 failed. Allylic alcohol 5
was therefore converted into the respective mesylate fol-
a) Pb(OAc)4
O
OH
b)
Oi-Pr
COOMe
MeO
O
OMe OH
MeO
4
PPh3
TIPSO
4
15
ΙΙΙ
N
H
OTIPS
c) LAH
82%
NHZ
O
OH OMe
MeO
MeO
14
Oi-Pr
OTIPS
OH
6
ΙΙ
OTBDMS
3
5
9
O
MeO
11
MeO
Oi-Pr
O
NH2
Oi-Pr
Ι
f)
MeO
Li
MeO
geldanamycin (1)
C9–C21 fragment (2)
7
Br
Oi-Pr
d) MsCl
e) LiBr
Scheme 1 Retrosynthesis of geldanamycin (1) leading to the C9–C21
fragment 2. Possible disconnections include carbonyl olefination (I),
enantioselective allyl transfer (II), and ring-closing metathesis (III).
Oi-Pr
14
CuBr·SMe2
90%
87%
MeO
MeO
OTIPS
OTIPS
Our own retrosynthetic plan to geldanamycin relies on the
idea of a ring closure between C4 and C5 by metathesis
(Scheme 1, step III).9,10 The stereogenic centers at C6 and
C7 are to be established by an enantioselective allyl
transfer9,11 (step II) and the double bond between C8 and
6
8
Scheme 2 Synthesis of the hydrogenation precursor 8 starting from
known D-mannitol-derived diol 3. Reagents and conditions: (a)
Pb(OAc)4 (1.05 equiv), Na2CO3 (1.0 equiv), CH2Cl2, 0 °C to r.t., 2 h,
98%; (b) 4 (2 equiv), toluene, reflux, 14 h, 86%; (c) LAH (1.2 equiv),
Et2O, 0 °C, 3 h, 97%; (d) MsCl (1.1 equiv), Et3N (2.0 equiv), CH2Cl2,
–50 °C to r.t.; (e) LiBr (4.0 equiv), Et2O–CH2Cl2, r.t., 10 h, 87% over
two steps; (f) 7 (4.0 equiv), CuBr·SMe2 (1.1 equiv), THF, –78 °C to
r.t., 90%.
SYNLETT 2008, No. 19, pp 2969–2972
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.11.2008
DOI: 10.1055/s-0028-1083625; Art ID: G27408ST
© Georg Thieme Verlag Stuttgart · New York

2970
T. Horneff, T. Bach
LETTER
lowed by halide exchange with lithium bromide. The io-
dide was available in a similar fashion, albeit in lower
yield (49%).
Table 1 Optimization of the Substrate-Controlled Diastereoselec-
tive Hydrogenation of Olefin 8 to the Desired Product 9a
Oi-Pr
Oi-Pr
MeO
MeO
The allylation to product 8 was carefully optimized. The
lithiation of 1,4-diisopropoxy-2-methoxybenzene with
butyllithium was complete within 45 minutes at room
temperature in THF solution. An uncatalyzed substitution
of bromide 6 with the lithiated arene 7 at 0 °C delivered
the desired product in yields up to 46%. The use of cu-
prates led partially to SN2¢-type substitution. The best re-
sult was observed when bromide 6 was treated with an
excess (4 equiv) of the lithiated arene 7 and stoichiometric
amounts of CuBr·SMe2.15 Exclusive SN2 substitution led
to product 8 in 90% yield.
H2, cat.
solvent
Oi-Pr
a: R1 = Me, R2 = H
b: R1 = H, R2 = Me
14
R1
R2
MeO
Oi-Pr
see Table 1
OTIPS
OMe
H
OTIPS
8
9
Entry H2 (bar)a Pressure
Catalyst
Concentration Solvent
(mol%)
dr
(9a/9b)b
1
2
50
1
Pd/C
10
10
10
10
10
10
5
EtOH
EtOH
EtOAc
THF
68:32
74:26
71:29
72:28
79:21
79:21
89:11
91:9
A diastereoselective hydrogenation of olefin 8 seemed
feasible based on its preferred conformation, which is dic-
tated by 1,3-allylic strain16 (Table 1). The small methoxy
group resides on one of the two diastereotopic faces (si-
face relative to C14), the bulky TIPSOCH2 group on the
other face. An attack was expected for steric reasons from
the si-face leading predominantly to product 9a. While
hydrogenation catalysts (PtO2, Pt/C, Raney-Ni, Ru on alu-
mina, Wilkinson catalyst) failed to deliver a reasonable
turnover at pressures of up to 80 bar in ethanol as the sol-
vent, Pd/C (entry 1) and Rh/C (entries 2–6) showed the
desired reactivity. The diastereoselectivity remained
moderate, however. The best results were obtained with
Rh/C at 70 or 80 bar (entries 5, 6) delivering a total yield
of 75% for 9.
Rh/C
3
1
Rh/C
4
1
Rh/C
5
70
80
1
Rh/C
EtOH
THF
6
Rh/C
7
Crabtreec
Crabtreec
Crabtreec
Crabtreec
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8
40
60
80
5
9
5
94:6
10
5
96:4
a Hydrogenation experiments were conducted at the given H2 pressure
and with the indicated catalyst at ambient temperature for 12 h.
b The 9a/9b dr was determined by GLC analysis.
c Crabtree catalyst = [Ir(cod)(PCy3)(py)]PF6; cod = 1,4-cyclooctadi-
ene.
Since products 9a and 9b were not separable at this stage
of the synthesis, the results with Rh/C were considered
unsatisfactory. Further catalyst screening revealed that the
use of [Ir(cod)PCy3(py)]PF6 (Crabtree catalyst)17 in
CH2Cl2 as the solvent (Table 1, entries 7–10) was the su-
perior choice. The coordination properties of the iridium
complex apparently enforce the desired approach from the
Si-face via the methoxy group.18 The diastereoselectivity
of the hydrogenation at atmospheric pressure (entry 7)
was already significantly higher than with any other pre-
viously employed catalyst and improved with increasing
pressure reaching a value of 96:4 for the diastereomeric
ratio at 80 bar (entry 10). The product 9 was isolated under
these conditions in 89% yield.
OH
R2 R1
R1
R2
MeO
O
a: R1 = Me, R2 = H
b: R1 = H, R2 = Me
O
MeO
OTIPS
10
11
Figure 1 Structures of the diastereoisomers a and b of alcohol 10
and of lactone 11, the latter (11a/11b) accessible from 10a/10b by
oxidation/ring closure
Attempts to prove the relative configuration of products
9a and 9b – beyond the given mechanistic hypothesis –
were not trivial. Eventually, it was achieved by a combi-
nation of chemical and NMR methods. Products 10 were
obtained from alcohol 5 by hydrogenation (H2, Raney-Ni,
EtOH, 55 bar, 110 °C, quant.), which occurred with low
diastereoselectivity (dr = 63:37). In this case, however,
the diastereomers were separable and could be converted
into lactones 11a and 11b (Figure 1), the relative config-
uration of which was determined by NOESY studies. Al-
cohols 10a and 10b could also be converted via the
corresponding iodides into products 9a and 9b, which al-
lowed for comparison and completed the desired configu-
ration proof.
With 9a in hand, the synthesis of fragment 2 was pursued
(Scheme 3). Deprotection of the silyl ether and subse-
quent oxidation with 2-iodoxybenzoic acid (IBX)19 deliv-
ered aldehyde 12, which underwent a smooth allyl-
transfer reaction with the chiral crotyl donor 13.20 Silyla-
tion of the resulting alcohol resulted in silyl ether 14.
Attempts to establish the two stereogenic centers at C-10
and C-11 by a substrate-induced diastereoselective allyl-
transfer process were not successful.21 The final steps of
the synthesis followed routes, which we had previously
employed for the synthesis of simple geldanamycin ana-
logues.9 The nitration22 occurred regioselectively in the
Synlett 2008, No. 19, 2969–2972 © Thieme Stuttgart · New York

LETTER
C9–C21 Fragment of Geldanamycin
2971
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Oi-Pr
MeO
Oi-Pr
MeO
e) Cu(NO3)2
f) NaBH4, S
g) ZCl
NHZ
Oi-Pr
Oi-Pr
69%
OTBDMS
OTBDMS
10
11
MeO
MeO
14
2
Scheme 3 Synthesis of the title compound 2 from hydrogenation
product 9a. Reagents and conditions: a) TBAF (3.0 equiv), THF, r.t.,
10 h, 83%; (b) IBX (3.0 equiv), EtOAc, 80 °C, 3 h; (c) 13 (3.0 equiv),
toluene, –78 °C, 20 h, 75% over two steps; (d) TBDMSOTf (2.5
equiv), Et3N (5.0 equiv), CH2Cl2, r.t., 3 h, 93%; (e) Cu(NO3)2·3H2O
(2.0 equiv), Ac2O, 0 °C, 1 h, 82%; (f) NaBH4 (16 equiv), S (56 equiv),
THF, 65 °C, 16 h, 97%; (g) ZCl (1.6 equiv), CH2Cl2–NaOH (aq), r.t.,
15 h, 87%.
position para to the methoxy group. Reduction with
NaBH4/S23 yielded the corresponding aniline, which was
Z-protected. The target compound 2 was isolated as a yel-
low oil.24
In summary, the C9–C21 fragment 2 of geldanamycin was
synthesized in a stereoselective fashion from D-mannitol-
derived diol 3 in 14 synthetic steps and an overall yield of
22%. The stereogenic center at C14 was established by a
diastereoselective Ir-catalyzed hydrogenation of olefin 8.
The stereogenic centers at C10 and C11 were created by
an enantioselective crotyl transfer reaction. Further stud-
ies are devoted to the use of fragment 2 for the synthesis
of geldanamycin analogues and of geldanamycin itself.
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Acknowledgment
Support of our research by the Deutsche Forschungsgemeinschaft
(DFG) and by the Fonds der Chemischen Industrie is gratefully ack-
nowledged. We thank the Wacker-Chemie AG (München) for the
generous donation of chemicals.
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References and Notes
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Synlett 2008, No. 19, 2969–2972 © Thieme Stuttgart · New York

2972
T. Horneff, T. Bach
LETTER
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J = 14.2, 10.3, 2.0 Hz, 1 H), 1.26 (d, J = 7.3 Hz, 6 H), 1.28
(d, J = 6.6 Hz, 6 H), 1.61 (ddd, J = 14.2, 10.7, 3.5 Hz, 1 H),
1.99–2.12 (m, 1 H), 2.18–2.28 (m, 1 H), 2.50 (dd, J = 12.8,
8.3 Hz, 1 H), 2.55 (dd, J = 12.8, 6.7 Hz, 1 H), 3.19 (ddd,
J = 10.7, 2.4, 2.0 Hz, 1 H), 3.23 (s, 3 H), 3.55 (dd, J = 7.9,
2.4 Hz, 1 H), 3.79 (s, 3 H), 4.07 (sept, J = 6.6 Hz, 1 H), 4.48–
4.62 (m, 1 H), 4.90–5.04 (m, 2 H), 5.20 (s, 2 H), 5.68 (ddd,
J = 17.2, 10.3 Hz, 8.5 Hz, 1 H), 7.13 (s, 1 H), 7.30–7.45 (m,
5 H), 7.60 (s, 1 H). 13C NMR (90.6 MHz, CDCl3): d = –4.8,
–4.0, 17.7, 18.5, 19.3, 22.2, 22.3, 22.5, 22.5, 26.1, 29.8, 33.6,
36.3, 41.9, 57.1, 60.5, 66.7, 70.9, 76.1, 76.3, 81.1, 104.2,
114.2, 127.6, 128.0, 128.1, 128.8, 136.4, 138.8, 141.7,
141.7, 144.5, 146.9, 153.3. IR (neat): 3432, 2971, 2928,
1738, 1602, 1514, 1471, 1436, 1382, 1372, 1224, 1196,
1111, 1069, 1030, 834, 776 cm–1. MS (ES+): m/z (%) = 732
(89), 690 (36), 672 (100). HRMS (ES+): m/z calcd for
C38H62NO7Si [M + H]+: 672.4290; found: 672.4276.
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d = –0.01 (s, 3 H), 0.01 (s, 3 H), 0.76 (d, J = 6.6 Hz, 3 H),
0.82–0.92 (m, 9 H), 1.05 (d, J = 6.8 Hz, 3 H), 1.15 (ddd,
Synlett 2008, No. 19, 2969–2972 © Thieme Stuttgart · New York