Stereoselective total synthesis of crucigasterins A, B and D through a common intermediate

Article abstract of DOI:10.1016/j.tetlet.2013.05.029

The first stereoselective total synthesis of the marine-derived antimicrobial amino-alcohols, crucigasterins A, B and D has been accomplished through a common intermediate starting from pent-3-en-1-ol. The method involves the Sharpless asymmetric aminohyd

Full text of DOI:10.1016/j.tetlet.2013.05.029

Accepted Manuscript
Stereoselective total synthesis of crucigasterins A, B and D through a common
intermediate
Jayprakash Narayan Kumar, Biswanath Das
PII:
S0040-4039(13)00786-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.029
TETL 42929
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
3 April 2013
7 May 2013
11 May 2013
Please cite this article as: Kumar, J.N., Das, B., Stereoselective total synthesis of crucigasterins A, B and D through
a common intermediate, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.029
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Graphical Abstract
Stereoselective total synthesis of crucigasterins
A, B and D through a common intermediate
Leave this area blank for abstract info.
Jayprakash Narayan Kumar and Biswanath Das*
NH2
OH
O
NH2
O
N
OH
OH
OH
O
NH2
OH

1
TETRAHEDRON
LETTERS
Tetrahedron Letters
Pergamon
journal homepage: www.elsevier.com
Stereoselective total synthesis of crucigasterins A, B and D through a common
intermediate†
Jayprakash Narayan Kumar and Biswanath Das *
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
500007
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first stereoselective total synthesis of the marine-derived antimicrobial
amino-alcohols, crucigasterins A, B and D has been accomplished through a
common intermediate starting from pent-3-en-1-ol. The method involves the
Sharpless asymmetric aminohydroxylation and Julia and Wittig olefinations as the
key steps.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Crucigasterins A, B and D, total synthesis,
asymmetric aminohydroxylation, Julia
olefination, Wittig olefination.
NH2
3
1
OH
NH2
NH2
The antimicrobial amino-alcohols, crucigasterins A-E (1-5)
4
O
were isolated from the Mediterranean colonial ascidian
2
3
OH
4
OH
Pseudodistoma crucigaster.1 The compounds bear
a close
O
N
OH
structural relationship – the length of the alkyl chains and the
number and geometry of the double bonds of these molecules are
different. Crucigasterin B (2) was found to posses both antifungal
and antibacterial properties at 50 µg/ml against Escherichia coli
and Candida albicans respectively. To our knowledge, the
synthesis of these molecules has not yet been reported.
6
O
OH
7
NH2
NH2
Scheme 1. Retrosynthetic route for crucigasterins A, B and D
3
4
2
1
OH
NH2
OH
NH2
The alcohol 7 was converted to its TBDPS ether (8) by
treatment with TBDPSCl and imidazole (Scheme 2). The double
3
bond of
8
was subjected to Sharpless asymmetric
3
4
OH
NH2
OH
aminohydroxylation3 using tBuOCONH2, (DHQ)2PHAL and
K2OsO4.2H2O to afford the aminoalcohol 9 along with its
regioisomer (ratio 7:3).
5
OH
In continuation of our work2 on the stereoselective
construction of bioactive natural products we report herein the
first total synthesis of crucigasterins A (1), B (2) and D (4)
through a common intermediate.
O
O
HN
O
O
N
b
OR
OTBDPS
c
OR
7
8
: R = H
: R = TBDPS
OH
O
a
9
10
6
: R = TBDPS
d
: R = H
The retrosynthetic analysis (Scheme 1) reveals that the
compounds 1, 2, and 4 can be synthesised from the common
intermediate 6 derived from pent-3-en-1-ol (7).
o
Scheme 2. Reagents and conditions: (a) Imidazole, CH2Cl2, TBDPSCl, 0 C-
rt, 30 min., 90%; (b) tBuOCONH2, NaOH, 1,3-dichloro-5,5-
dimethylhydantoin, (DHQ)2PHAL, K2OsO4.2H2O, 21 h, 65%, 94% ee; (c)
Corresponding author, Tel./fax: +91 40 27160512;
E-mail: biswanathdas@yahoo.com
o
2,2-DMP, CH2Cl2, p-TsOH (catalytic), 0 C-rt, 30 min., 82%; (d) TBAF (1.5
equiv), THF, 0 oC-rt, 3 h, 95%.
These isomers were not separated at this stage. The aminoalcohol
9 was protected by 2,2- DMP in the presence of p-TsOH to form

2
1
the acetonide 10.4 The ether group of 10 was cleaved by TBAF to
generate the required intermediate 6.
olefinic protons of this double bond in the H NMR spectrum.
The acetonide deprotection of 22 followed by the deprotection of
the amine group yielded the naturally occurring crucigasterin B
(2). The structure of the compound was confirmed from its
spectral data.1
For synthesis of crucigasterin A (1) the intermediate 6 was
oxidized with IBX and the corresponding aldehyde was subjected
to C-2 Wittig olefination using Ph3PCHCOOEt to afford the
unsaturated ester 11 (Scheme 3).5 The ester 11 was reduced with
DIBAL-H to produce the alcohol 12. The alcohol 12 was again
oxidized with IBX6 and the respective aldehyde underwent Julia
olefination using benzothiazolyl sulfone 13 and KHMDS to
furnish the triene 14.7 The acetonide group of 14 was deprotected
to generate 15 by treatment with a methanolic solution of p-
TsOH. At this stage the triene 14 was purified to separate from its
regioisomer. Finally, the deprotection of the amine group of 15
by TFA afforded crucigasterin A (1). Its spectral data revealed
the structure of the compound.1
O
O
O
N
O
N
a
OH
4
22
O
6
O
NH2
b
4
2
OH
Scheme 5. Reagents and conditions: (a) (i) IBX, DMSO, CH2Cl2; (ii) 21 (2.5
equiv), n-BuLi (2.5 equiv), THF, 0 oC, 15 min, then –80 oC, aldehyde, 2 h, rt,
2 h, 65% (over two steps), (E:Z = 07:93); (b) (i) p-TsOH (catalytic), MeOH;
(ii) TFA, CH2Cl2, 88% over two steps.
O
O
O
N
O
N
a
The synthesis of 21 was started from octane-1,8-diol (24) (Scheme 6).
One of the hydroxyl groups of 24 was protected as its TBS ether (25)
and the ether hydroxyl group was oxidized under Swern conditions.
The corresponding aldehyde was subjected to C-1 Wittig olefination to
afford the olefin 26. The TBS ether group of 26 was deprotected with
TBAF to generate the alcohol 27. The latter was reacted with CBr4 to
form the bromo compound 28 which on treatment with PPh3 produced
the desired phosphonium salt 21.
b
OH
OEt
6
11
O
O
O
O
O
O
N
O
N
c
d
OH
3
14
12
O
O
O
NH2
O
NH
e
3
3
1
15
OH
b
OH
OR
e
R
PPh
3 Br
HO
24 : R = H
21
26
27
: R = OTBS
: R = OH
a
c
25 : R = TBS
Scheme 3. Reagents and conditions: (a) (i) IBX, DMSO, CH2Cl2, (ii) C2-
Wittig, benzene, reflux, 2 h, 87% over two steps, E:Z = 95:5; (b) DIBAL-H
(2.5 equiv), CH2Cl2, –78 oC, 2 h, 85%; (c) (i) IBX, DMSO, CH2Cl2; (ii) 13
(1.2 equiv), aldehyde (1 equiv), THF, KHMDS (1 equiv), 65% over two
steps, E:Z = 83:17; (d) p-TsOH (catalytic), MeOH, 90%; (e) TFA, CH2Cl2,
92%.
d
28
: R = Br
Scheme 6. Reagents and conditions: (a) NaH, TBSCl, THF, 0 oC-rt, 80%; (b)
o
i) (COCl)2, DMSO, Et3N, CH2Cl2, –78 C; ii) C-1Wittig, n-BuLi, THF, –78
oC, 75% over two steps; (c) TBAF, THF, 0 oC- rt, 87%; (d) PPh3, CBr4,
imidazole, CH2Cl2, –30-30 oC, 76%; (e) PPh3, neat, heating, 92%.
The synthesis of the sulfone 13 was started with hexane-1,6-
diol (16) (Scheme 4). One of the hydroxyl groups of the latter
was protected as TBS ether (17) by treatment with TBSCl and
NaH. The free hydroxyl group of 17 was subjected to Swern
oxidation and the corresponding aldehyde underwent C-1 Wittig
olefination with methylene triphenyl phosphonium ylide using n-
BuLi to generate the olefin 18. The ether group of 18 was
deprotected with TBAF and the resulting alcohol 19 was treated
with mercaptobenzothiazole (MBT) to produce 20 which was
oxidized with H2O2 in the presence of ammonium molybdate to
furnish the required sulfone 13.7
The intermediate 6 was again utilized for the synthesis of
crucigasterin D (4) (Scheme 7). The former was oxidized with
IBX and the corresponding aldehyde underwent Julia olefination
with the benzothiazolyl sulfone 29 to afford the diene 30.
Subsequent deprotection of the acetonide group of 30 followed
by deprotection of the amine functionality produced the natural
amino-alcohol, crucigasterin D (4). The spectral properties of the
compound agreed well with its structure.1
O
O
d
b
R
OR
HO
O
N
O
N
18 : R = OTBS
19
16
17
a
: R = H
b
OH
c
a
3
: R = OH
: R = TBS
O
30
O
6
O
S
NH2
N
S
N
e
O
S
3
S
4
OH
Scheme 7. Reagents and conditions: (a) (i) IBX, DMSO, CH2Cl2; (ii) 29 (1.2
equiv), aldehyde (1 equiv), THF, KHMDS (1 equiv), 70%, (E:Z = 79:21); (b)
(i) p-TsOH (catalytic), MeOH; (ii) TFA, CH2Cl2, (90% overall yield).
Scheme 4. Reagents and conditions: (a) NaH, TBSCl, THF, 0 oC-rt, 75%; (b)
o
i) (COCl)2, DMSO, Et3N, CH2Cl2, –78 C; ii) C-1Wittig, n-BuLi, THF, –78
o
oC, 70%; (c) TBAF, THF, 0 C-rt, 87%; (d) TPP, MBT, DIAD,THF, 0oC-rt,
89%; (e) (NH4)2MoO4, H2O2, EtOH, 0 oC-rt, 90%.
For the synthesis of the sulfone 29 butane-1,4-diol (32) was
used as the starting material (Scheme 7). One of the two hydroxyl
groups of 32 was protected as TBS ether (33). The free hydroxyl
group of the latter was oxidized under Swern conditions and the
corresponding aldehyde was subjected to Wittig olefination with
(CH2)6CHPPh3 to produce the olefin 34.8 TBS ether group of 34
was deprotected with TBAF and the respective alcohol 35 was
For the synthesis of crucigasterin B (2) the intermediate 6 was
again oxidized with IBX (Scheme 5) and the respective aldehyde
was subjected to Wittig olefination with phosphonium ylide 21 to
form the diene 22.8 The newly generated double bond in 22 was
in the cis-form as decided by the nature of the signals of the two

3
treated with MBT to furnish 36 which under oxidation with H2O2
in the presence of ammonium molybdate produced the required
sulfone 29.
7. (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans I.
2002, 2563. (b) Vazquez-Romero, A.; Cardenas, L.;
Blasi, E.; Verdaguer, X.; Riera, A. Org. Lett. 2009, 11,
3104.
b
d
OR
HO
OR
34 : R = TBS
32 : R = H
8. (a) Zanoni, G.; Brunoldi, E. M.; Porta, A.; Vidari, G. J.
Org. Chem. 2007, 72, 9698. (b) Herdeis, C.; Telser, J.
Eur. J. Org. Chem. 1999, 1407. (c) Sarabia, F.; Garcia-
Castro, M.; Chammaa, S. Tetrahedron Lett. 2005, 46,
7695.
a
c
35
: R = H
33 : R = TBS
N
N
O
S
O
e
S
S
S
3
3
29
36
9. Spectroscopic data for selected compounds are given
below.
Scheme 8. Reagents and conditions: (a) NaH, TBSCl, THF, 0 oC-rt, 65%; (b)
o
i) (COCl)2, DMSO, Et3N, CH2Cl2, –78 C, 95%; ii) (CH2)6CHPPh3, n-BuLi,
THF, –78 oC, 80%, (E:Z = 4:96); (c) TBAF, THF, 0 oC-rt, 88%; d) TPP,
MBT, DIAD, THF, 0 oC-rt, 87%; (e) (NH4)2MoO4, H2O2, EtOH, 0 oC-rt, 92%.
Compound 6: Yellow oil, Rf
=
0.4 (20%
1
EtOAc/Hexane). H NMR (200 MHz, CDCl3): ꢀ 3.85-
3.70 (3H, m), 3.49 (1H, m), 2.38 (1H, m), 1.88-1.70
(2H, m), 1.49-1.38 (15H, brs), 1.21 (3H, d, J = 7.0 Hz);
13C NMR (50 MHz, CDCl3): ꢀ 151.9, 94.5, 80.0, 79.3,
60.2, 57.9, 35.8, 28.4, 14.1; ESIMS: m/z 282 [M + Na]+,
HRESIMS: cald. m/z 282.16737, found m/z 282.16758.
In conclusion, we have accomplished the first stereoselective
total synthesis of the marine derived antimicrobial amino-
alcohols, crucigasterins A, B, and D through a common
intermediate using the easily available, pent-3-en-1-ol as the
starting material. The synthesis involves the Sharpless
asymmetric aminohydroxylation and Julia and Wittig olefinations
as the key steps. The method can convincingly be utilized for the
synthesis of different crucigasterin analogues useful for their
bioevaluation.
Compound 13: Yellow liquid, Rf
= 0.7 (10%
EtOAc/hexane). 1H NMR (200 MHz, CDCl3): ꢀ 6.38
(1H, m), 6.12-5.92 (2H, m), 5.82 (1H, m), 5.60 (1H, m),
5.04-4.80 (2H, m), 3.73 (1H, m), 3.51 (1H, m), 2.43-
2.31 (2H, m), 2.10-1.99 (4H, m), 1.62-1.53 (4H, m),
1.51-1.42 (15H, brs), 1.23 (3H, d, J = 7.0 Hz ); 13C
NMR (50 MHz, CDCl3): ꢀ 151.9, 139.0, 133.5, 131.1,
130.0, 128.3, 114.2, 93.2, 81.1, 79.8, 57.3, 36.8, 33.8,
33.6, 32.6, 32.4, 28.4, 14.1; ESIMS: m/z 386 [M +
Na]+, HRESIMS: cald. m/z 386.26694, found m/z
386.26657.
Acknowledgements:
The authors thank CSIR and UGC, New Delhi for financial
assistance.
References and notes:
†Part 65 in the series, “Synthetic studies on natural products”
Compound 20: Yellow liquid, Rf
= 0.8 (10%
EtOAc/hexane). 1H NMR (200 MHz, CDCl3): ꢀ 5.58
(1H, m), 5.43-5.32 (2H, m), 5.11-5.02 (2H, m), 4.12
(1H, m), 3.72 (1H, m), 2.41-2.28 (4H, m), 2.09-1.92
(2H, m), 1.63-1.51 (8H, m), 1.48 (6H, s), 1.30 (9H, s),
0.87 (3H, t, J = 7.0 Hz ); 13C NMR (200 MHz, CDCl3):
ꢀ 159.1, 130.7, 129.2, 123.9, 113.8, 94.3, 82.0, 79.7,
55.2, 34.1, 31.9, 31.4, 30.2, 29.7, 29.3, 28.4, 25.2, 22.7,
14.1; ESIMS: m/z 388 [M + Na]+. Anal. Cald. for
C22H39NO3: C, 72.28; H, 10.75; N, 3.83. Found: C,
72.24; H, 10.78; N, 3.86.
1. Ciavatta, M. L.; Manzo, E.; Nuzzo, G.; Villani, G.;
Varcamonti, M.; Gavagnin, M. Tetrahedron 2010, 66,
7533.
2. (a) Sudhakar, Ch.; Reddy P. R.; Kumar, G. C.; Sujitha,
P.; Das, B. Eur. J. Org. Chem. 2012, 1253. (b)
Kashanna, J.; jangili, P.; Kumar, R. A.; Das, B. Helv.
Chem. Acta 2012, 95, 1666. (c) Reddy, G. C.;
Balasubhramanyu, P.; Salvanna, N.; Reddy, T. S.; Das,
B. Biorg. Med. Chem. Lett. 2012, 22, 2415.
3. (a) Demko, Z. P.; Bartsch, M.; Sharpless, K. B.
Organic let. 2000, 2, 2221. (b) Lohray, B. B.;
Thombare, P. S.; Bhusan, V. Proc. Ind. Nat. Sci. Acad.
2002, 68, 391. (c) Bodkin, J. A.; Mcleod, M. D. J.
Chem. Soc., perkin trans I. 2002, 2733.
Compound 27: Yellow oil, Rf
=
0.7 (10%
1
EtOAc/hexane). H NMR (200 MHz, CDCl3): ꢀ 5.53-
5.28 (4H, m), 3.98 (1H, m), 3.47 (1H, m), 2.51-2.25
(2H, m), 2.14-1.92 (6H, m), 1.65-1.52 (2H, m), 1.44
(12H, s), 1.38-1.16 (12H, brs), 0.88 (3H, t, J = 7.0 Hz );
13C NMR (50 MHz, CDCl3): ꢀ 152.1, 133.2, 132.4,
130.7, 129.0, 94.1, 81.4, 79.3, 57.2, 36.8, 32.7, 31.7,
29.6, 28.9, 28.4, 27.3, 27.0, 22.6, 13.9; ESIMS: m/z 416
[M + Na]+, HRESIMS: cald. m/z 416.31383, found m/z
416.31352.
4. Shaikh, N. S.; Bhur, S. S.; Gajare, A. S.; Despande, V.
H.; Wakharkar, R. D. Tetrahedron let. 2004, 45, 5395.
5. Das, B.; Suneel, K.; Satyalakshmi, G.; Kumar, D. N.
Tetrahedron: Asymmetry 2009, 20, 1536.
6. (a) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
(b) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T.
Angew Chem. 2003, 115, 4211.
Compound 1: Yellow oil, Rf
=
0.2 (90%
25
EtOAc/hexane). [ꢁ]D = −4.2 (c = 0.25, CHCl3/MeOH
5:1); 1H NMR (200 MHz, CDCl3): ꢀ 6.01 (1H, m), 5.89-

4
5.70 (2H, m), 5.61 (1H, m), 5.36 (1H, m), 5.05-4.88
(2H, m), 4.12 (1H, m), 3.66 (1H, m), 2.38-2.27 (2H, m),
2.11-1.96 (6H, m), 1.70-1.52 (2H, m), 1.48-1.37 (2H,
m), 0.82 (3H, d, J = 7.0 Hz ); 13C NMR (50 MHz,
CDCl3): ꢀ 138.9, 133.5, 131.0, 130.0, 128.3, 114.3,
81.0, 51.5, 36.7, 33.8, 33.6, 32.6, 32.4, 14.1; ESIMS:
m/z 224 [M + H]+, HRESIMS: cald. m/z 224.20114,
found m/z 224.20089.
Compound 2: Yellow oil, Rf
=
0.2 (80%
25
EtOAc/hexane). [ꢁ]D = −3.6 (c = 0.25, CHCl3/MeOH
5:1); 1H NMR (200 MHz, CDCl3): ꢀ 5.62 (1H, m), 5.44-
5.25 (2H, m), 5.11-5.02 (2H, m), 4.65 (1H, brs), 4.14
(1H, m), 3.42 (1H, m), 2.41-2.27 (4H, m), 2.10-1.91
(4H, m), 1.22 (9H, s), 0.85 (3H, t, J = 7.0 Hz ); 13C
NMR (200 MHz, CDCl3): ꢀ 138.1, 133.2, 126.5, 113.6,
81.0, 52.1, 34.1, 30.8, 30.0, 29.8, 29.6, 28.2, 14.1;
ESIMS: m/z 226 [M + H]+. Anal. Cald. for C22H39NO3:
C, 74.61; H, 12.08; N, 6.21. Found: C, 74.64; H, 12.11;
N, 6.26.
Compound 4: Yellow oil, Rf
=
0.2 (80%
25
EtOAc/hexane). [ꢁ]D = −5.1 (c = 0.25, CHCl3/MeOH
5:1); 1H NMR (200 MHz, CDCl3): ꢀ 5.60-5.22 (4H, m),
4.50 (1H, brs), 4.16 (1H, m), 3.62 (1H, m), 2.40-2.21
(2H, m), 2.13-1.91 (6H, m), 1.70-1.53 (2H, m), 1.35-
1.22 (6H, m), 0.91-0.80 (6H, m); 13C NMR (50 MHz,
CDCl3): ꢀ 134.1, 130.5, 128.8, 124.9, 81.5, 51.6, 37.0,
34.1, 32.8, 31.8, 29.6, 29.4, 29.0, 27.3, 22.6, 14.1;
ESIMS: m/z 254 [M + H]+, HRESIMS: cald. m/z
254.24791 [M + H]+, found m/z 254.24784.