An asymmetric synthesis of sulfobacin A

Article abstract of DOI:10.1016/j.tetlet.2007.03.115

A facile synthesis of sulfobacin A has been developed starting from (R)-cyclohexylideneglyceraldehyde (11). The key steps in the synthesis are the highly diastereocontrolled allylation of 11 and syn-selective reduction of a ketone derived from 11. The oth

Full text of DOI:10.1016/j.tetlet.2007.03.115

Tetrahedron Letters 48 (2007) 3705–3707
An asymmetric synthesis of sulfobacin A
Anubha Sharma, Sunita Gamre and Subrata Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 5 January 2007; revised 12 March 2007; accepted 21 March 2007
Available online 25 March 2007
Abstract—A facile synthesis of sulfobacin A has been developed starting from (R)-cyclohexylideneglyceraldehyde (11). The key steps
in the synthesis are the highly diastereocontrolled allylation of 11 and syn-selective reduction of a ketone derived from 11. The other
attractive features are the operational simplicity and the use of inexpensive compounds/reagents.
Ó 2007 Elsevier Ltd. All rights reserved.
The development of simple and efficient strategies is a
highly desirable goal for organic synthesis. Despite
impressive progress,1a this remains a very dynamic and
challenging area in asymmetric synthesis.1b,c The most
practical methods are aimed at producing target com-
pounds via reliable routes utilizing inexpensive and
readily available materials. To this end, we have recently
reported expeditious syntheses of various bioactive
compounds such as prelactone B,2a herbarumin III,2b
oxybutynin,2c safingol2d and hapalosin2e,f, using easily
accessible (R)-cyclohexylideneglyceraldehyde 11 as a
chiral template. This Letter reports an efficient asym-
metric synthesis of sulfobacin A starting from 11.
The synthesis of 1a essentially requires amidation of the
chiral b-hydroxy acid A with amino alcohol B, both pos-
sessing the same long chain aliphatic moiety (Scheme 1).
It was envisaged that fragment A could be constructed
by allylation of 112b and introduction of the aliphatic
chain at the acetal site. Given that amino alcohol B is
an alkyl glycerol derivative, its synthesis from 11 also
appeared straightforward. Thus, the total synthesis
could be divided into the four parts discussed below.
For the syntheses of the long chain aliphatic synthons,
the known ketone 35 prepared from the commercially
available inexpensive acid 2 was converted to ester 4
by a Wittig reaction with triphenylmethylphosphonium
iodide (72%) followed by catalytic hydrogenation
(ꢀquant.). Ester 4 was reduced with LAH to alcohol 5
(95%), which was brominated to furnish 6 (91%), the re-
quired synthon for the preparation of A. Likewise, C-
alkylation of 7,6 accessible from 2, with 2-bromopro-
pane and subsequent depyranylation gave 8 (85% in
two steps). Catalytic hydrogenation to 9 (ꢀquant.) fol-
lowed by bromination afforded 10 (92%) (Scheme 2).
Sulfobacins A and B (1a and 1b) were isolated indepen-
dently from the culture broth of the soil grown bacte-
rium strain Chryseobacterium sp. NR 2933,3a,b while
1a was also obtained from the marine bacterium Flavo-
bacterium sp., isolated from the marine bivalve Cristaria
plicata.3c Besides being potent DNA polymerase a
inhibitors, 1a and 1b also show potent competitive
inhibitory activity against the binding of von Willebrand
factor to the GPIb/1X receptor with IC50 values of
0.47 lM and 2.2 lM, respectively. The compounds be-
long to the class of sulfonolipids having an aminosulf-
onic acid moiety, and are analogous to sphingosine. In
view of their impressive bioactivity and unusual struc-
tures, several syntheses of sulfobacins A and B involving
combinations of chemical/enzymatic asymmetric routes
or chiral building blocks have been reported.4
O
OH
SO3H
O
OH
OH
(CH2)11
A
(CH2)11
OH
N
H
(CH2)11
SO3H
1a
(CH2)11
SO3H
HN
O
OH
H
(CH2)11
OH
(CH2)11
N
H
B
1b
*
Corresponding author. Tel.: +91 22 25593703; fax: +91 22
5505151; e-mail: schatt@barc.gov.in
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.115

3706
A. Sharma et al. / Tetrahedron Letters 48 (2007) 3705–3707
O
i
ii,iii
iv
(CH2)8CO2H
(CH2)8CO2Me
(CH2)8CO2Me
(CH2)9X
2
3
4
5 X = OH
6 X = Br
v
vi
vii
iii
HC
C
(CH2)9OTHP
C
C (CH2)9OH
(CH2)11X
7
8
9 X = OH
10 X = Br
v
Scheme 2. Reagents and conditions: (i) Ref. 5, (ii) MePPh3I/n-BuLi/THF/ꢁ20 °C (72%), (iii) H2/10% Pd–C/EtOH/rt (ꢀquant.), (iv) LAH/Et2O/D
(95%), (v) Ph3P/Br2/pyridine/CH2Cl2 (91%), (vi) Ref. 6, (vii) n-BuLi/THF/HMPA/(CH3)2CHBr/ꢁ78 °C; MeOH/PTS/D (85%).
For the preparation of synthon A, homoallylic alcohol
12 obtained almost exclusively (91%, syn:anti = 3:97)
by allylation7 of aldehyde 11 was benzylated to give 13
(93%). Deacetalization with aqueous trifluoroacetic acid
(TFA) gave diol 14 (72%), which was converted into
epoxide 15 (86%) via regioselective monotosylation
and base treatment. The Cu+-catalyzed reaction of 15
with the Grignard reagent prepared from 6 proceeded
smoothly to furnish 16 (84%). Mesylation of 16 followed
by LAH reduction gave 17 (81%). This was converted to
acid 18 (92%) by NaIO4/RuCl3-catalyzed oxidative
cleavage8 of the alkene function (see Scheme 3).
To prepare synthon B, the Grignard reagent prepared
from 10 was reacted with 11 to give alcohol 19 with a
predominance of the anti-isomer (81:19 anti:syn). Since
O
OH
O
iv
O
iii
i
HO
O
O
CHO
OBn
15
OBn
14
OR
12 R = H
13 R = Bn
11
ii
OH
O
OBn
OBn
v
vi
vii
(CH2)10
OH
(CH2)11
18
(CH2)11
OBn
16
17
O
O
O
(CH2)11
OR
O
x
viii
ix
11
O
(CH2)11
O
(CH2)11
O
syn-19 R = H
21 R = Bn
OH
19
ii
20
N3
OH
OH
xii
TBSO
(CH2)11
xi
iii
TBSO
(CH2)11
HO
(CH2)11
OBn
24
OBn
23
OBn
22
NHBoc
(CH2)11
NHR
xvii
xv
R
xiii
TBSO
xiv
(CH2)11
OBn
27 R = OH
28 R = SCOCH3
OBn
25 R = H
26 R = Boc
xvi
SO3H
O
OH
R
O
OBn
xix,xx
(CH2)11
OH
(CH2)11
(CH2)11
OBn
N
(CH2)11
xviii
N
H
H
1a
29 R = SCOCH3
30 R = SH
Scheme 3. Reagents and conditions: (i) Allyl bromide/Zn/aqueous NH4Cl/0 °C (91%), (ii) NaH/BnBr/THF/D (93%), (iii) aqueous TFA/rt (72%),
(iv) p-TsCl/pyridine; K2CO3/MeOH (86%), (v) 6/Mg/THF/CuBr/ꢁ78 °C (84%), (vi) MsCl/pyridine/CH2Cl2/0 °C; LAH/Et2O/D (81%), (vii) NaIO4/
RuCl3,H2O (cat.)/CCl4–CH3CN–H2O (92%), (viii) 10/Mg/THF/0 °C–rt (86%), (ix) PCC/NaOAc/CH2Cl2/rt (92%), (x) K-Selectride/THF/ꢁ78 °C
(93%), (xi) TBSCl/triethylamine/4,4-dimethylaminopyridine/CH2Cl2/rt (91%), (xii) MsCl/pyridine/0 °C–rt; NaN3/DMF/D (86%), (xiii) Ph3P/
MeOH/D (87%), (xiv) Boc2O/triethylamine/4,4-dimethylaminopyridine/THF/rt (93%), (xv) TBAF/THF/ꢁ78 °C (97%), (xvi) MsCl/triethylamine/
CH2Cl2; CH3COSK/DMF/rt (89%), (xvii) aqueous HCl–dioxane; 18/DCC/DMAP/TEA/DMF/ꢁ10 °C–rt (79%), (xviii) LAH/Et2O/0 °C (80%),
(xix) H2/10% Pd-C/EtOH/rt (95%), (xx) 30% aqueous H2O2/TFA/rt (39%).

A. Sharma et al. / Tetrahedron Letters 48 (2007) 3705–3707
3707
Sharma, A.; Roy, S.; Goswami, D.; Chattopadhyay, A.;
Chattopadhyay, S. Lett. Org. Chem. 2006, 3, 741.
the syn-isomer was required for the synthesis, the diaste-
reomeric mixture of 19 was oxidized with pyridinium
chlorochromate (PCC, 92%) to afford ketone 20. Reduc-
tion of 20 with K-Selectride proceeded with absolute
diastereocontrol to afford pure syn-19 in 93% yield.9
Benzylation to 21 (95%) followed by TFA-catalyzed
deacetalization gave diol 22 (81%). Regioselective silyla-
tion of the primary hydroxyl group gave 23 (91%),
which on mesylation and subsequent azidation with
inversion afforded 24 (86%).9 Reduction of the azide
function with Ph3P gave amine 25 (87%), Boc-protection
of which afforded 26 (93%). Desilylation with tetrabutyl-
ammonium fluoride (TBAF) furnished alcohol 27 (97%),
which on mesylation and subsequent reaction with
CH3COSK afforded 28 (89%).
3. (a) Kamiyama, T.; Umino, T.; Satoh, T.; Sawairi, S.;
Shirane, M.; Ohshima, S.; Yokose, K. J. Antibiot. 1995, 48,
924; (b) Kamiyama, T.; Umino, T.; Itezono, Y.; Nakamura,
Y.; Satoh, T.; Yokose, K. J. Antibiot. 1995, 48, 929; (c)
Kobayashi, J.; Mikami, S.; Shigemori, H.; Takao, T.;
Shimonishi, Y.; Izuta, S.; Yoshida, S. Tetrahedron 1995, 51,
10487.
4. (a) Irako, N.; Shirori, T. Tetrahedron Lett. 1998, 39, 5793;
(b) Irako, N.; Shirori, T. Tetrahedron Lett. 1998, 39, 5797;
(c) Shirori, T.; Irako, N. Tetrahedron 2000, 56, 9129; (d)
Takikawa, H.; Muto, S.; Nozawa, D.; Kayo, A.; Mori, K.
Tetrahedron Lett. 1998, 39, 6931; (e) Takikawa, H.;
Nozawa, D.; Kayo, A.; Muto, S.-E.; Mori, K. J. Chem.
Soc., Perkin Trans. 1 1999, 2467; (f) Labeeuw, O.; Phan-
savath, P.; Genet, J.-P. Tetrahedron Lett. 2003, 44, 6383; (g)
Labeeuw, O.; Phansavath, P.; Genet, J.-P. Tetrahedron:
Asymmetry 2004, 12, 1899; (h) Gupta, P.; Naidu, S. V.;
Kumar, P. Tetrahedron Lett. 2004, 45, 9641.
5. Sankaranarayanan, S.; Sharma, A.; Kulkarni, B. A.;
Chattopadhyay, S. J. Org. Chem. 1995, 60, 4251.
6. Kulkarni, B. A.; Chattopadhyay, S.; Chattopadhyay, A.;
Mamdapur, V. R. J. Org. Chem. 1993, 58, 5964.
7. Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104, The syn-
and anti-isomers of 12 could be easily separated by normal
chromatography (silica gel, 0–15% EtOAc/hexane).
8. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, B. J.
Org. Chem. 1981, 46, 3936.
Synthesis of the target compound 1a was achieved as
follows. N-deprotection of 28 followed by a dicyclohexyl
carbodiimide (DCC)-catalyzed condensation with 18
gave amide 29 (79%). This was converted to thiol 30
(80%) by reduction with LAH at low temperature. This
on debenzylation (95%) by catalytic hydrogenation fol-
lowed by oxidation with H2O2–TFA led to the target
compound 1a in 39% yield.
In conclusion, an efficient asymmetric synthesis of
sulfobacin A has been developed from easily available
(R)-cyclohexylideneglyceraldehyde using a set of diaste-
reoselective transformations.
9. All the compounds were fully characterized from their
spectral, optical and microanalytical data. Representative
25
data is included. Data for syn-19: colourless oil; ½aꢂD +12.4
(c 0.9, CHCl3); IR: 3456, 1478, 1372 cmꢁ1 1H NMR
;
(CDCl3, 200 MHz): d 0.85 (d, J = 6.8 Hz, 6H), 1.23 (s,
17H), 1.26–1.50 (m, 8H), 1.58–1.62 (m, 8H), 2.23 (br s, 1H),
3.45–3.49 (m, 1H), 3.58–3.75 (m, 1H), 3.90–4.03 (m, 2H);
13C NMR (CDCl3, 50 MHz): d 22.4, 23.5, 23.7, 23.8, 24.9,
25.3, 27.2, 27.7, 29.4, 29.7, 33.5, 34.6, 36.1, 38.8, 65.6, 72.2,
78.6, 109.6. Anal. Calcd for C23H44O3: C, 74.95; H, 12.03.
References and notes
1. (a) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.;
Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 44; (b) Corey,
E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
388; (c) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; New York: Wiley, 1994.
2. (a) Salaskar, A.; Mayekar, N. V.; Sharma, A.; Chattopa-
dhyay, A.; Nayak, S. K.; Chattopadhyay, S. Synthesis 2005,
2777; (b) Salaskar, A.; Sharma, A.; Chattopadhyay, S.
Tetrahedron: Asymmetry 2006, 17, 325; (c) Roy, S.; Sharma,
A.; Chattopadhyay, N.; Chattopadhyay, S. Tetrahedron
Lett. 2006, 47, 7067; (d) Sharma, A.; Gamre, S.; Chatto-
padhyay, S. Tetrahedron Lett. 2007, 48, 633; (e) Mula, S.;
Chattopadhyay, S. Lett. Org. Chem. 2006, 3, 54; (f)
25
Found: C, 75.12; H 12.12. Data for 24: colourless oil; ½aꢂD
+8.2 (c 1.22, CHCl3); IR: 3065, 3031, 2096 cmꢁ1; 1H NMR
(CDCl3, 200 MHz): d 0.08 (s, 6H), 0.86 (d, J = 6.8 Hz, 6H),
0.91 (s, 9H), 1.26 (s, 18H), 1.43–1.58 (m, 5H), 3.48–3.55 (m,
2H), 3.71–3.77 (m, 2H), 4.53 (d, J = 11.4 Hz, 1H), 4.61 (d,
J = 11.4 Hz, 1H), 7.25–7.46 (m, 5H); 13C NMR (CDCl3,
50 MHz): d ꢁ5.5, 18.2, 22.7, 25.1, 25.3, 25.8, 27.4, 28.0,
29.7, 30.0, 30.8, 39.1, 63.3, 65.4, 72.4, 78.0, 127.7, 127.9,
128.4, 138.2. Anal. Calcd for C30H55N3O2Si: C, 69.58; H,
10.70; N, 8.11. Found: C, 69.48; H, 10.84; N, 8.27.