Stereoselective synthesis of the C1-C20 segment of the microsclerodermins A and B

Article abstract of DOI:10.1016/j.tetlet.2006.07.107

An enantioselective route for the synthesis of key fragment C1-C20 resident in microsclerodermins A and B is described. The route features deoxygenative rearrangement of an hydroxy-alkynoate and a highly enantio- and diastereo-controled iterative dihydrox

Full text of DOI:10.1016/j.tetlet.2006.07.107

Tetrahedron Letters 47 (2006) 7255–7258
Stereoselective synthesis of the C1–C20 segment of the
microsclerodermins A and BI
S. Chandrasekhar* and S. Shameem Sultana
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 29 May 2006; revised 10 July 2006; accepted 21 July 2006
Available online 22 August 2006
Abstract—An enantioselective route for the synthesis of key fragment C1–C20 resident in microsclerodermins A and B is described.
The route features deoxygenative rearrangement of an hydroxy-alkynoate and a highly enantio- and diastereo-controled iterative
dihydroxylation as key reactions, starting from S-(ꢀ)-citronellol.
Ó 2006 Elsevier Ltd. All rights reserved.
The microsclerodermins (A–I) are a class of natural
products, isolated from the lithistid sponge Microsclero-
derma sp., that display significant antifungal and anti-
tumor activities.1 Of the nine bioactive metabolites in this
family, microsclerodermins A and B are two of the most
biologically active with antifungal activity against Can-
dida albicans (at 2.5 lg/disk). The microsclerodermins
A and B have a complex molecular structure, compris-
ing a 23-membered cyclic hexapeptide core, featuring
four unusual amino acid residues, one of which is a very
complex b-amino acid residue located in the C1–C20
region. This fragment has five contiguous asymmetric
centers at C2–C6. Due to its biological profiles and
the dense presence of stereogenic centers in the C1–
C20 region, the target microsclerodermins A and B
demand effective control of distal asymmetric induction,
rendering the stereoselective preparation of this
antifungal agent a challenging problem in chemical
synthesis. To date only one research group has contrib-
uted to the partial synthesis of this complex natural
product.2
the application of iterative Sharpless asymmetric dihydr-
oxylation (SADH) on diene ester 3. This, in turn could
be obtained by triphenylphosphine-mediated rearrange-
ment of alkynol 4 which was to be synthesized from
commercially available S-(ꢀ)-citronellol 5 (Scheme 1).
As illustrated in Scheme 2, stereoselective synthesis of
the C1–C20 segment of microsclerodermins A and B
commenced with S-(ꢀ)-citronellol 5, as a suitable chiral
substrate.
The S-(ꢀ)-citronellol 5 was protected as its tetrahydro-
pyranyl ether 6. Compound 6 was subjected to ozono-
lysis to furnish aldehyde 7, which was elaborated to
unsaturated ester 8 by Wittig olefination. The stepwise
reduction of the conjugate olefin (Mg–MeOH) followed
by ester reduction to primary alcohol 9 was achieved
using LiAlH4.3 The primary alcohol group in 9 was pro-
tected as a benzyl ether 10 by treatment with NaH and
benzyl bromide in 90% yield. The selective release of
one of the primary alcohols was achieved by using p-
TSA in MeOH to realize 11. This allowed us to extend
the ‘right-hand’ side of the fragment. The oxidation of
11 using IBX4 furnished aldehyde 12, which was imme-
diately exposed to lithiated ethylpropiolate to realize the
formation of hydroxy alkynoate 4 as a diastereomeric
mixture, which was not separated. The critical diene
ester intermediate 3 was obtained from 4 by triphenyl-
phosphine-mediated deoxygenative rearrangement via
an allene.5 This rearrangement allowed us to obtain
the diene ester ready for the stereoselective incorpora-
tion of hydroxy groups via iterative Sharpless asymmet-
ric dihydroxylation.
In this letter, we describe an efficient synthesis of the
C1–C20 subunit resident in microsclerodermins A and
B. Our retrosynthetic analysis envisioned the late install-
ment of the four contiguous stereocenters of 2 through
Keywords: Stereoselective; Deoxygenative rearrangement; Iterative
Sharpless asymmetric dihydroxylation.
q IICT Communication No: 060525.
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
27160512; e-mail: srivaric@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.107

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S. Chandrasekhar, S. S. Sultana / Tetrahedron Letters 47 (2006) 7255–7258
37
H
R=OH: microsclerodermin A
R= H: microsclerodermin B
N
O
30
47
COOH
R
O
HN
32
H
N
28
40
N
O
42
N
OH
H
O
1
O
NH
OH
O
H
N
OH
OH
20
OMe
26
O
18
N
3
21
11
H
5
1
HO
14
19
OMOM
OH
O
O
NHBoc
BnO
CO2Et
2
3
C1-C20 segment
MeO
OH
BnO
OH
4
CO2Et
(S)-(-)-citronellol
5
Scheme 1.
a
(S)-(-)-Citronellol
b
OTHP
5
6
H
c
OTHP
OTHP
MeO2C
7
8
O
d,e
g
RO
OTHP
9, R = H
10, R = Bn
f
OH
i
X
BnO
BnO
4
CO2Et
CO2Et
11, X = CH2OH
12, X = CHO
h
j
k
BnO
CO2Et
3
OH
HO
O
O
CO2Et
CO2Et
l
BnO
BnO
13
14
Scheme 2. Reagents, conditions and yields: (a) Dihydropyran, p-TSA (5 mol %), CH2Cl2, rt, 2 h, 98%; (b) O3, DMS, CH2Cl2, ꢀ78 °C; (c)
Ph3P@CHCOOMe, benzene, rt, 84% (for two steps); (d) Mg/MeOH, rt, 12 h, 86%; (e) LiAlH4, THF, 0 °C–rt, 96%; (f) BnBr, NaH, THF, 0 °C–rt,
90%; (g) p-TSA (5 mol %), MeOH, rt, 2 h, 93%; (h) IBX, DMSO-THF, rt, 3 h, 95%; (i) LiHMDS, THF, ꢀ78 °C, 2 h, 86%; (j) Ph3P, benzene, rt, 90%;
t
(k) AD mix-aMeSO2NH2, BuOH–H2O (1:1), 0 °C, 24 h; (l) 2,2 DMP, CSA (5 mol %), DCM, 1 h, 85%.
At first glance, Sharpless asymmetric dihydroxylation
followed by a Sharpless asymmetric aminohydroxyl-
ation reaction seemed to be an option to establish the
required four stereogenic centers at C2-3 and C4-5 in
2. The enantio- and regio-selective Sharpless asymmetric
dihydroxylation6 of diene ester 3 with AD mix-a in
tBuOH:H2O (1:1) provided the diol 13 which was
masked as its acetonide 14 using 2,2-dimethoxypropane
and catalytic camphorsulfonic acid (CSA) in 85% yield
(for two steps) with 96% de. The major isomer was sep-
arated by column chromatography (Scheme 3).
The regioselective incorporation of a cis-aminohydroxyl
group was planned as the next step by Sharpless asym-
metric aminohydroxylation,7 however, this method
was unsuccessful. Thus, we envisaged an asymmetric

S. Chandrasekhar, S. S. Sultana / Tetrahedron Letters 47 (2006) 7255–7258
7257
OH
O
OH
O
O
O
OH
CO2Et
a
c
b
14
BnO
OH
BnO
OH
15
16
O
O
O
O
O
O
O
O
O
O
O
O
NHBoc
g
e,f
X
BnO
N3
BnO
OR
19
17, R = H
18, R = Tf
20, X = CH2OH
21, X = CHO
d
h
OH
O
O
O
OR
O
O
O
m
NHBoc
k
i,j
NHBoc
23, R = H
24, R = OTBS
l
22
MeO
MeO
OMOM
OH
O
OMOM
OTBS
O
O
O
n
NHBoc
NHBoc
2
25
MeO
C1-C20 segment
MeO
Scheme 3. Reagents, conditions and yields: (a) AD-mix-b, tBuOH:H2O, 0 °C, 87%; (b) LiAlH4, THF, 1 h, 0 °C–rt, 80%; (c) 2,2-DMP, CSA
(5 mol %), DCM, rt, 85%; (d) Tf2O, pyridine, DCM, ꢀ10 °C; (e) Bu4NBr, DCM, rt, 86% (for two steps); (f) NaN3, DMF, 65 °C, 4 h, 82%; (g)
Pd(OH)2/C–H2, (Boc2)O, MeOH, 92%; (h) IBX, DMSO:THF, 3 h, 88%; (i) 4-CH3O–C6H4CH2P + Ph3Clꢀ, n-BuLi, THF, 12 h, 0°C–rt, 70%; (j)
Pd(CH3CN)2Cl2, DCM (0.5 M), rt, 92%; (k) PPTS, MeOH, 45 °C, 12 h, 75%; (l) TBSCl, imidazole, DMAP (3 mol %), DCM, 82%; (m) MOMCl,
DIPEA, DCM, rt, 90%; (n) TBAF, THF, rt, 70%.
dihydroxylation-double inversion (at C-3) sequence. A
second, Sharpless asymmetric dihydroxylation8 on 14,
with the diastereomerically matched chiral reagent AD
mix-b in BuOH–H2O at 0 °C afforded the diol 15 in
87% yield with excellent diastereoselectivity (10:1).
Unfortunately, efforts to introduce the amine function-
ality at C-3 always produced only the elimination
product.9
hyde 21 with (4-methoxyphenylmethylene) triphenyl-
phosphorane in THF was used to provide a mixture of
E/Z isomers in a ratio of 3:2 in 70% yield. Treatment
of the mixture of isomers with a catalytic amount of
Pd(CH3CN)2Cl2 in 0.5 M DCM at room temperature
caused isomerization11 of the double bond and afforded
t
1
the isomerically pure E-isomer 22 in 92% yield. The H
NMR spectrum showed a doublet at d 6.29 ppm
(J = 15.8 Hz) and a multiplet at 6.05–5.95 ppm which
provided confirmation for the E-geometry.
To avoid the competitive elimination reaction, the di-
hydroxy ester 15 was reduced to triol 16 with LiAlH4 in
THF. Then, the triol 16 was subjected to regioselective
1,2-acetonide protection with 2,2-DMP in DCM using
CSA to give 17 in 85% yield. Treatment of the diaceto-
nide 17 with Tf2O in the presence of pyridine gave tri-
flate 18. The sequential displacement of the triflate 18
by bromide (Bu4NBr) followed by azide (NaN3) pro-
vided the nitrogen function with overall retention of
configuration10 at C-3. The required five contiguous
asymmetric centers at C2–C6 for the key building block
2 had now been established by the synthesis of azido
compound 19.
The terminal acetonide in 22 was selectively deprotected
under mildly acidic conditions (PPTS in MeOH)12 to
give the diol 23. The two liberated hydroxyl groups were
protected selectively. A TBS group was introduced
regioselectively at the primary hydroxyl group to yield
24. Introduction of methoxymethyl at the remaining free
hydroxyl group was achieved by the reaction of 24 with
MOMCl and diisopropylethylamine in DCM to obtain
25 in 90% yield. The conditions for the regioselective re-
moval of the TBS protecting group from 25 were inves-
tigated next, and was possible, utilizing TBAF in THF,
to provide the key fragment 2,13 which could be oxidized
at a later stage. All these transformations completed the
stereoselective synthesis of the C1–C20 segment of
microsclerodermins A and B.
At this point, a one-pot deprotection–reduction–protec-
tion strategy was utilized. The azide 19 was subjected to
Pd(OH)2/C catalyzed hydrogenation in the presence of
(Boc)2O which effected benzyl ether deprotection, azide
reduction and Boc-protection of the resulting amine to
afford compound 20 in 92% overall yield. The alcohol
20 was oxidized with IBX to furnish the desired alde-
hyde 21 in 88% yield. For the construction of the styryl
moiety of compound 3, Wittig alkenation of the alde-
In conclusion, we have developed an efficient, enantio-
selective route for the synthesis of the C1–C20 fragment
resident in microsclerodermins A and B. The route fea-
tures a deoxygenative rearrangement of an alkynol, and
an highly enantio- and diastereo-controled iterative

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S. Chandrasekhar, S. S. Sultana / Tetrahedron Letters 47 (2006) 7255–7258
10. (a) Ward, R. S.; Pelter, A.; Goubet, D.; Pritchard, M. C.
Tetrahedron: Asymmetry 1995, 6, 469–498; (b) Bernsmann,
H.; Wang, Y.; Frohlich, R.; Metz, P. Tetrahedron 2002,
58, 4451–4457; (c) Raghavan, S.; Rasheed, M. A. Tetra-
hedron: Asymmetry 2003, 14, 1371–1374; (d) Scriven, E.;
Turnbull, K. Chem. Rev. 1988, 88, 297–368.
11. Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002,
67, 4627–4629.
12. Rijsbergen, R. V.; Anteunis, R. M. J. O.; Bruyn, A. D. J.
Carbohydr. Chem. 1983, 2, 395.
dihydroxylation as key reactions starting from S-(ꢀ)-
citronellol. Further progress towards the total synthesis
of 1 is currently ongoing in our laboratory.
Acknowledgements
S.S.S. thanks CSIR, New Delhi for financial support
and S.C. thanks DST, New Delhi for a grant.
13. Representative analytical data: Compound 3: Colorless
25
oil; ½aꢁD 31.5 (c 1.45, CHCl3). 1H NMR (300 MHz,
CDCl3): 1H NMR (300 MHz, CDCl3): d 7.32–7.18 (m,
6H), 6.14–5.91 (m, 2H), 5.71 (d, 1H, J = 15.1 Hz), 4.45 (s,
2H), 4.13 (q, 2H, J = 7.5 Hz), 3.41 (t, 2H, J = 6.0 Hz),
2.27–2.18 (m, 1H), 1.62–1.53 (m, 2H), 1.39–1.22 (m, 9H),
1.01 (d, 3H, J = 6.7 Hz). 13C NMR (75 MHz, CDCl3): d
165.0, 150.0, 145.0, 138.5, 128.2, 127.4, 127.3, 126.4, 119.2,
72.7, 70.2, 59.9, 36.9, 36.3, 29.5, 26.9, 26.1, 19.8, 14.1. ESI-
MS: m/z 331 [M++1]. HRMS calcd for C21H31O3:
331.1933 (M++1); found: 331.1926.
References and notes
1. (a) Bewley, C.; Debitus, C.; Faulkner, D. J. J. Am. Chem.
Soc. 1994, 116, 7631–7636; (b) Qureshi, A.; Colin, P. L.;
Fulkner, D. J. Tetrahedron 2000, 56, 3679–3685.
2. (a) Sasaki, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett.
1997, 38, 3013–3016; (b) Sasaki, S.; Hamada, Y.; Shioiri,
T. Tetrahedron Lett. 1999, 40, 3187; (c) Sasaki, S.;
Hamada, Y.; Shioiri, T. Synlett 1999, 4, 453–455.
3. Chandrasekhar, S.; Reddy, M. V. Tetrahedron 2000, 56,
1111–1114.
4. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
8019–8022.
5. Guo, C.; Lu, X. J. Chem. Soc.,Chem. Commun. 1993, 394–
395.
25
Compound 14: Colorless oil; ½aꢁD ꢀ935 (c 0.75, CHCl3).
1H NMR (200 MHz, CDCl3): d 7.24 (m, 5H), 6.76 (dd,
1H, J = 5.7 Hz, J = 4.9 Hz), 6.02 (d, 1H, J = 15.5 Hz),
4.45 (s, 2H), 4.28–4.12 (m, 3H), 3.53 (t, 1H, J = 6.5 Hz),
3.37 (t, 2H, J = 6.5 Hz), 1.76–1.12 (m, 18H), 0.93 (d, 3H,
J = 7.3 Hz). 13C NMR (75 MHz, CDCl3): d 164.9, 144.4,
137.6, 127.2, 126.4, 126.3, 121.4, 108.0, 83.7, 78.4, 71.7,
69.2, 59.3, 34.6, 31.6, 28.6, 26.0, 25.5, 25.2, 14.7, 13.0.
(ESI-MS): m/z 427 [M++Na]. HRMS calcd for
C24H36O5Na: 427.2563 (M++Na), found: 427.2569.
6. Xu, D.; Crispino, G.; Sharpless, K. B. J. Am. Chem. Soc.
1992, 114, 7570–7571.
7. (a) Li, G.; Chang, H. T.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 1996, 35, 451–455; For a review on asymmetric
aminohydroxylation, see: (b) Bodkin, J. A.; McLeod, M.
D. J. Chem. Soc., Perkin Trans. 1 2002, 2733–2746.
8. Gao, D.; O’Doherty, G. A. Org. Lett. 2005, 6, 1069–1072.
9. The introduction of the azide functionality at C-3 was
planned by another asymmetric dihydroxylation-double
inversion (at C-3) sequence. Unfortunately, this method
resulted in the elimination product 15b.
25
Compound 20: Colorless oil; ½aꢁD ꢀ1733 (c 0.5,
CHCl3). 1H NMR (300 MHz, CDCl3): d 4.99 (bs,1H),
4.04–3.98 (m, 1H), 3.84–3.81 (m, 1H), 3.76–3.71 (m, 1H),
3.62–3.57 (m, 3H), 3.60–3.40 (m, 2H), 1.70–1.13 (m, 30H),
0.96 (d, 3H, J = 6.7 Hz). 13C NMR (75 MHz, CDCl3): d
155.7, 109.3, 109.2, 85.0, 80.0, 79.6, 79.1, 76.3, 62.7, 42.7,
35.5, 32.7, 31.3, 28.3, 27.4, 27.0, 26.7, 25.9, 16.3.
(ESI-MS): m/z 468 [M++Na]. HRMS calcd for
C23H43NO7Na: 468.2364 (M++Na), found: 468.2370.
25
Compound 2: Colorless oil; ½aꢁD ꢀ1073 (c 1.4, CHCl3). 1H
OBz
CO2Et
O
NMR (300 MHz, CDCl3): d 7.21 (d, 2H, J = 9.0 Hz), 6.78
(d, 2H, J = 8.6 Hz), 6.30 (d, 1H, J = 15.3 Hz), 6.06–5.96
(m, 1H), 4.94–4.89 (br s, 1H), 4.69 (s, 2H), 4.20–3.87 (m,
3H), 3.78 (s, 3H), 3.54–3.05 (m, 6H), 2.23–2.14 (m, 2H),
1.67–1.17 (m, 22H), 0.95 (d, 3H, J = 6.0 Hz). 13C NMR
(100 MHz, CDCl3): d 158.8, 130.8, 130.6, 129.1, 128.7,
126.9, 113.8, 109.3, 97.6, 83.9, 79.3, 79.2, 70.6, 68.0, 56.2,
55.2, 43.2, 36.2, 32.9, 31.2, 28.3, 27.5, 27.3, 26.5, 16.4.
(ESI-MS): m/z 552 [M++1]. HRMS calcd for C30H50O8N:
552.2719 (M++1), found: 552.2722.
O
(a) BzCl, TEA, DMAP (cat),
-78 ºC, 12 h, 90%;
15
BnO
Br
(b) Tf2O, Py, DCM
15a
(c) Bu4NBr, DCM, rt
OH
O
O
CO2Et
(d) NaN3, DMF, r.t, 4 h
82%
BnO
15b