Synthesis of the C23-C32 fragment of spirangien

Article abstract of DOI:10.1016/j.tetlet.2007.02.081

The synthesis of the C23-C32 fragment of spirangien A is reported using Evans' alkylation, Evans-Metternich aldol reaction and a substrate controlled stereoselective reduction.

Full text of DOI:10.1016/j.tetlet.2007.02.081

Tetrahedron Letters 48 (2007) 2905–2907
Synthesis of the C23–C32 fragment of spirangien
Michael Lorenz and Markus Kalesse*
Leibniz Universita¨t Hannover, Institut fu¨r Organische Chemie, Schneiderberg 1B, D-30167 Hannover, Germany
Received 8 January 2007; revised 14 February 2007; accepted 16 February 2007
Available online 22 February 2007
Abstract—The synthesis of the C23–C32 fragment of spirangien A is reported using Evans’ alkylation, Evans–Metternich aldol
reaction and a substrate controlled stereoselective reduction.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
mLꢀ1) and for 3 (IC50 = 7 ng/mLꢀ1) (Fig. 2) has been
observed.1
Myxcobacteria are a valuable source for the isolation of
structurally diverse biologically active natural products.
Among the various strains isolated from Sorangium
cellulosum, strain So ce90 produces important antibiotic
and cytotoxic compounds such as epothilone. Spiran-
gien A (1) and B (2) (Fig. 1) were isolated from the
same strain1 and have been tested for their biological
activity. They show high activity against yeast and fungi
(e.g., diameters of inhibition zones: Pichia membra-
naefaciens 24 mm, Rhodotorula glutins 19 mm, Botrytis
cinerea 11 mm).1 Additionally, high cytotoxicity of 1
against L929 mouse fibroblast cell line (IC50 = 0.7 ng/
Ho¨fle and co-workers elucidated the structures of these
two spirangiens A (1) and B (2) by NMR spectroscopy
and mass spectrometry. They contain a highly function-
alised spiroketal core structure, a side chain bearing a
pentaene chromophore, a terminal carboxyl group and
a total of 14 stereocentres. Through a cross metathesis
reaction 1 was shortened to segment 3 of which X-ray
31
acetal formation
27
HO
H
R
O
15
O
H
12
31
22
MeO
MeO
OH
CO2H
3
HO
19
3
27
9
5
HO
aldol
H
O
O
H
15
12
22
OH OH OH
O
OH OH
MeO
31
OH
19
HO
12
19
27
15
22
OH
Spirangien A (1): R = CH3
Spirangien B (2): R = CH2CH3
4
reduction
O
(relative Configuration for C14 to C28
)
TES
O
TBS
O
O
OH OH
Figure 1. Spirangien A (1) and B (2).
31
19
25
12
15
22
OH
5
Keywords: Evans alkylation; Substrate controlled stereoselective
6
reduction; Evans–Metternich aldol.
Evans-Metternich
Evans' alkylation
*
Corresponding author. Tel.: +49 0 511 762 4688; fax: +49 0 511 762
3011; e-mail addresses: michael.lorenz@oci.uni-hannover.de;
Markus.Kalesse@oci.uni-hannover.de
Figure 2. Retrosynthesis of 3.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.081

2906
M. Lorenz, M. Kalesse / Tetrahedron Letters 48 (2007) 2905–2907
1. (R)-9, Bu2BOTf, NEt3
analysis was utilised to determine the relative
configuration.
TBS
2. TBSOTf, 2,6-lutidine
O
OH
,
3. LiBH4 EtOH
6% over three steps
12
Our retrosynthetic analysis dissects 3 at the spiroketal
moiety to the open chain fragment 4 (Fig. 2). This in
turn can be assembled by an aldol addition of ketone
6 to aldehyde 5 (Fig. 2). Here, we report the synthesis
of the C23–C32 fragment 5 of spirangien.
15
TBS
O
1. DMP
O
O
O
2. (S)-9, Bu2BOTf, NEt3
3. DMP
26
27
N
O
8% over three steps
Bn
14
The synthesis of aldehyde 5 (Scheme 1) starts with the
commercially available tiglic acid (7) which is reduced2
quantitatively to the corresponding alcohol with LiAlH4
and subsequently transformed into bromide 8 using
PBr3 and pyridine for buffering the reaction mixture.3
Scheme 2. Alternative route to synthesise 14.
TBS TES
O
O
O
O
,
1. Zn(BH4)2 61%
Bromide 8 is then employed in an Evans’ alkylation2
using oxazolidinone 9. Deprotonation with NaHMDS
as the base results in high yields and stereoselectivity
to provide 10. Reductive cleavage of the Evans auxiliary
with LiBH4 in methanol4 followed by oxidation with
DMP leads to aldehyde 12 (Scheme 1). Next, a syn selec-
tive Evans–Metternich aldol5 reaction with auxiliary 13,
in the presence of freshly prepared Sn(OTf)2 and NEt3
yields the product in a diastereomeric ratio of 1.7:1 in
favour of the desired product. A similar highly syn selec-
tive aldol addition using tin enolates was described by
Evans and co-workers.5 TBS protection allowed separa-
tion of the diastereomers of ketone 14 cleanly (Scheme
1). This protocol generates 14 in a very good yield over
three steps starting from DMP oxidation of 11.
2. TESOTf, 2,6-lutidine, 96%
14
N
O
16
Bn
TBS
TES
O
O
OH
LiBH4, MeOH, 85%
17
Scheme 3. Final steps for the synthesis of 17.
pared Zn(BH4)2 to furnish b-hydroxy ketone 18 in
moderate yields (Scheme 4).7 The reducing reagent is
ideally suited for a highly coordinating transition state.
The two oxygens in this a-methyl-b-ketoamide are coor-
dinated by Zn(BH4)2 such that the hydride attacks from
the side opposite to the a-methyl group. This yields the
desired syn product as described by Oishi, Evans and
co-workers.8 TES-protection of the alcohol at C25 and
reductive cleavage of the Evans auxiliary with LiBH4
in methanol yield alcohol 17 (Scheme 3).
The stereochemistry at C26 and C27 was confirmed by
the synthesis of 14 via two syn selective Evans aldol
reactions6 and TBS-protection of the free alcohol
(Scheme 2) followed by comparison of optical rotations
and NMR spectroscopy of a mixture of 14 which were
synthesised through two different routes (Schemes 1
and 2). Nevertheless, the previous route via the Evans–
Metternich aldol reaction was identified advantageous
due to the poor yields in the two subsequent Evans aldol
reactions.
In order to additionally confirm the relative configura-
tion of the diol at C25 and C27 TBS deprotection of
18 to produce diol 19 followed by acetonide formation
utilising 2,2-dimethoxypropane9 results in the formation
of 20 which shows indicative 13C NMR shifts for the
methyl groups and the quaternary carbon at d = 24.6,
25.7 and 102.1 ppm, respectively (Scheme 4) confirming
the expected 1,3-anti configuration of the diol.
A stereoselective substrate controlled reduction of
ketone 14 at C25 can be achieved by using freshly pre-
In summary, we have achieved the efficient and selective
synthesis of the C23–C32 segment of spirangien with an
Evans–Metternich aldol and a substrate controlled
O
1. LiAlH4 quant.
,
2. PBr pyridine, 52%
,
3
(R)-9, NaHMDS, 83%
OH
Br
7
8
O
O
OH
1. HF*pyridine,
pyridine, 29%
LiBH4, MeOH, 89%
DMP
N
O
O
OR OH
O
2. 2,2-dimethoxypropane,
PPTS, 96%
10
11
N
O
O
Bn
TBS
O
O
O
O
O
O
1. Sn(OTf)2 NEt3, 13
2. TBSOTf, 2,6-lutidine
57% over 3 steps
Bn
R = TBS, 18
R = H, 19
26
1.
27
O
N
12
Bn
14
O
O
O
O
O
O
O
N
O
N
O
N
O
Bn
20
(R)-9
Bn
13
Bn
Scheme 4. Synthesis of acetal 20 to confirm the relative configuration
Scheme 1. Synthesis of ketone 14.
at C25 and C27.

M. Lorenz, M. Kalesse / Tetrahedron Letters 48 (2007) 2905–2907
2907
stereoselective reduction using Zn(BH4)2 in the key
steps. The C23–C32 segment will serve as the pivotal
substrate for completing the synthesis of this natural
product and to provide analogues for detailed SAR
studies.
NaHCO3-solution, brine, dried over MgSO4 and con-
centrated in vacuo. Flash chromatography (EtOAc/hex-
anes 1:25) yielded alcohol 17 (13 mg, 27.5 lmol, 85%).
20
Rf = 0.28 (EtOAc/hexanes 1:25); ½aꢁ589 ꢀ7.32 (c 1.1
CHCl3); 1H NMR (400 MHz, CDCl3) d = 5.18 (q,
J = 6.3 Hz, 1H), 3.77 (dd, J = 6.3, 0.5 Hz, 1H), 3.57 (t,
J = 3.1 Hz, 1H), 3.44–3.52 (m, 2H), 2.11 (q, J =
9.1 Hz, 1H), 1.81–1.85 (m, 2H), 1.71–1.80 (m, 2H),
1.59 (s, 3H), 1.57 (s, 3H), 1.25–1.28 (m, 1H), 0.97 (t,
J = 8.0 Hz, 9H), 0.91 (s, 9H), 0.89 (d, J = 3.8 Hz, 3H),
0.87 (d, J = 3.4 Hz, 3H), 0.78 (d, J = 6.1 Hz, 3H), 0.63
(q, J = 8.0 Hz, 6H), 0.07 (d, J = 3.4 Hz, 6H); 13C
NMR (100 MHz, CDCl3) d = 134.3, 119.9, 74.6, 67.1,
41.9, 41.2, 37.9, 36.9, 26.2, 18.6, 15.7, 15.5, 13.4, 12.0,
11.1, 7.1, 5.6, ꢀ3.5, ꢀ3.6; HRMS (ESI, C26H57O3
[M+H+]) calculated: 473.3768; found: 473.3875.
2. Experimental
2.1. Acetal 20
To a solution of 19 (7.0 mg, 16.8 lmol) in CH2Cl2
(1 mL) 2,2-dimethoxypropane (55 lL, 425 lmol) and
PPTS (0.5 mg, cat.) were added at 0 °C. The mixture
was stirred for 16 h and satd aq NaHCO3-solution was
added. The aqueous layer was extracted with CH2Cl2
and the organic layer was washed with water, dried over
MgSO4 and concentrated in vacuo. Purification via flash
chromatography (EtOAc/hexanes 1:5) yielded 20 as a
colourless oil (7 mg, 16.2 lmol, 96%). Rf = 0.22
References and notes
20
1
1. Niggemann, J.; Bedorf, N.; Flo¨rke, U.; Steinmetz, H.;
Gerth, K.; Reichenbach, H.; Ho¨fle, G. Eur. J. Org. Chem.
2005, 5013–5018.
2. Clive, D. L. J.; Murthy, K. S. K.; Wee, A. G. H.; Prasad, J.
S.; da Silva, G. V. J.; Majewski, M.; Anderson, P. C.;
Evans, C. F.; Haugen, R. D.; Heerze, L. D.; Barrie, J. R.
J. Am. Chem. Soc. 1990, 112, 3018–3028.
3. Lauchenauer, A.; Schinz, H. Helv. Chim. Acta 1951, 183,
1514–1523.
4. Pilli, R. A.; Russowsky, D. J. Org. Chem. 1996, 61, 3187–
3190.
5. (a) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V.
J.; Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866–
868; (b) Evans, D. A.; Kim, A.; Metternich, R.; Novack, V.
J. J. Am. Chem. Soc. 1998, 120, 5921–5942; (c) Evans, D.
A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757–
6761.
6. Evans, D. A.; Palniaszek, R. P.; DeVries, K. M.; Guinn, D.
E.; Mathre, D. J. J. Am. Chem. Soc. 1991, 113, 7613–7630.
7. (a) Evans, D. A.; Trenkle, W. C.; Zhang, J.; Burch, J. D.
Org. Lett. 2005, 7, 3335–3338; (b) Paquette, L. A. In
Encyclopedia of Reagents for Organic Synthesis; John Wiley
& Sons: NY, 1995; Vol. 8, 5536.
8. (a) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338–344;
(b) Evans, D. A.; Ennis, M. D.; Le, T. J. Am. Chem. Soc.
1984, 106, 1154, and references cited therein.
9. (a) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I.
Acc. Chem. Res. 1998, 31, 9; (b) Evans, D. A.; Rieger, D.
L.; Gage, J. R. Tetrahedron Lett. 1990, 31, 7099–7100; (c)
Patterson, I.; Temal-Laib, T. Org. Lett. 2002, 15, 1273–
2476.
(EtOAc/hexanes 1:5); ½aꢁ589 +39.6 (c 0.70 CHCl3); H
NMR (400 MHz, CD3OD) d = 7.26–7.38 (m, 5H),
5.23 (q, J = 6.6 Hz, 1H), 4.71–4.77 (m, 1H), 4.28–4.35
(m, 2H), 4.03–4.09 (m, 1H), 3.66 (dd, J = 5.9, 5.6 Hz,
1H), 3.38 (dd, J = 10.3, 3.8 Hz, 1H), 3.18 (dd,
J = 13.4, 3.2 Hz, 1H), 3.01 (dd, J = 13.5, 8.2 Hz, 1H),
2.58 (d, J = 13.2 Hz, 1H), 1.98–2.04 (m, 1H), 1.65–1.72
(m, 1H), 1.62 (d, J = 6.5 Hz, 3H), 1.59 (s, 3H), 1.49
(dd, J = 13.1, 10.9 Hz, 1H), 1.35 (s, 3H), 1.33 (s, 3H),
1.29 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.74
(d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CD3OD)
d = 176.6, 155.4, 137.2, 135.9, 131.0, 130.1, 128.5,
121.3, 102.1, 77.7, 75.5, 67.9, 57.1, 45.2, 43.0, 38.6,
36.9, 32.3, 27.5, 25.7, 24.6, 15.9, 14.9, 13.8, 12.8; HRMS
(ESI, C27H40O5N [M+H+]) calculated: 458.2906; found:
458.2901.
2.2. Alcohol 17
To a solution of the diprotected alcohol 16 (21 mg,
32.5 lmol) in THF (1 mL) methanol (500 lL) and
LiBH4 (2 M in THF, 49 lL, 97.6 lmol) were added
dropwise at 0 °C. The mixture was warmed to rt and
stirred for 2 h. The solution was then cooled to 0 °C
and another portion of LiBH4 (2 M in THF, 49 lL,
97.6 lmol) was added. After stirring for additional 2 h
at rt aq NaOH-solution (2 M) was added. The organic
layer was extracted with CH2Cl2, washed with satd aq