The first total synthesis of SB87-Cl and pestalone, novel bioactive benzophenone natural products

Article abstract of DOI:10.1016/j.tetlet.2004.05.063

SB87-Cl 1, an inhibitor of testosterone-5α-reductase, and pestalone 2 exhibiting effective antimicrobial activity against MRSA (MIC=37ng/mL) and VRE (MIC=78ng/mL), were novel bioactive benzophenone natural products. Total synthesis of 1 and 2 has been successfully accomplished. The common synthetic precursor 18 of 1 and 2, was successfully obtained by the coupling of 8 with 12.

Full text of DOI:10.1016/j.tetlet.2004.05.063

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5469–5471
The first total synthesis of SB87-Cl and pestalone, novel
bioactive benzophenone natural products
Daisuke Iijima, Daisuke Tanaka, Motoko Hamada, Takahisa Ogamino,
Yuichi Ishikawa and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku,
Yokohama 223-8522, Japan
Received 15 April 2004; revised 6 May 2004; accepted 7 May 2004
Abstract—SB87-Cl 1, an inhibitor of testosterone-5a-reductase, and pestalone 2 exhibiting effective antimicrobial activity against
MRSA (MIC ¼ 37 ng/mL) and VRE (MIC ¼ 78 ng/mL), were novel bioactive benzophenone natural products. Total synthesis of 1
and 2 has been successfully accomplished. The common synthetic precursor 18 of 1 and 2, was successfully obtained by the coupling
of 8 with 12.
Ó 2004 Elsevier Ltd. All rights reserved.
In connection with the male-disorder caused by 5a-
dihydrotestosterone, which is reductively produced from
testosterone, some inhibitors of testosterone-5a-reduc-
tase have been reported. However, their steroidal or
related structures exhibited undesired hormone actions.
In this context, SB87-Cl 1,1 isolated from the genus
Chrysosporium as an inhibitor of the reductase, has a
different structural feature from other inhibitors, which
would be expected for safe use of an active ingredient of
hair growth stimulants. On the other hand, pestalone 2,2
obtained from the mixed fermentation broth of Pest-
alotia sp. CNL-365 and CNJ-328, exhibited highly
potent antimicrobial activity against methicillin-resis-
tant Staphylococcus aureus (MRSA) (MIC ¼ 37 ng/mL)
and vancomycin-resistant Enterococcus faecium (VRE)
(MIC ¼ 78 ng/mL). Accordingly, 2 would be a new lead
against such drug-resistant strains.
would enable their extensive chemical and biological
investigation. We describe herein our investigation
process.
Retrosynthetically, the common highly functionalized
benzophenone framework of 1 and 2 would be divided
into two aromatic derivatives, A and B (Scheme 1). The
prenyl side chain and formyl group of fragment A might
be introduced by ortho-lithiation of the oxazoline
derivative, produced from 3,5-dihydroxybenzoic acid 3,
which might also be a precursor of B. The Schmalz
group employed closely similar strategy, and they
reported the difficulty of introduction of the formyl
group at the final stage.3
Synthesis of fragment A (8) was initiated from oxazoline
4,4 produced from 3,5-dihydroxybenzoic acid
3
(Scheme 2). The process involving methoxycarbonyl-
ation, reduction, TBS protection, and subsequent pren-
ylation was unsuccessful, probably owing to steric
hindrance. Therefore, the order of functionalization was
switched; 4 was prenylated first, and then a methoxy-
carbonyl group was successfully introduced to 5, leading
to ester 6 in 62% yield. After reduction, the corre-
sponding alcohol was protected as a TBDPS ether.
Reductive deprotection4;5 of oxazoline 7 afforded the
desired aryl aldehyde 8.
In spite of their closely similar structures, 1 and 2
exhibited entirely different bioactivities. Although syn-
thesis of deformyl analogues of 2 has been reported by
Schmalz and Kaiser,3 2 itself, as well as 1 has not been
synthesized to date. To understand their diverse mode of
action, we initiated total synthesis of 1 and 2, which
Keywords: SB87-Cl; Testosterone-5a-reductase; Chrysosporium; Pest-
alone; Pestalotia; MRSA; VRE.
Fragment B (12) was also synthesized from 3 (Scheme
3); after exhaustive protection by benzyl groups, the
* Corresponding author. Tel./fax: +81-45-566-1717; e-mail: nisiyama@
chem.keio.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.063

5470
D. Iijima et al. / Tetrahedron Letters 45 (2004) 5469–5471
OP
Cl
O
OH
Cl
PO
CHO
OP
Cl
Li
HO
Cl
+
PO
CHO RO
OP
OH
fragment A
fragment B
SB87-Cl 1 R = H
pestalone 2 R = Me
N
CO2H
PO
O
HO
OH
OP
3
Scheme 1. Structures and retrosynthesis of SB87-Cl 1 and pestalone 2.
OBn
N
e, f
a, b
BnO
O
3
X
a
ref. 4
BnO
3
OBn
9 X = OH
10 X = H
c, d
4
N
R
OH
OMOM
Cl
BnO
N
Cl
O
Br
MOMO
ref. 3, 6
BnO
O
HO
OBn
Cl
Cl
OBn
6 R = CO2Me
5
11
c, d
12
7 R = CH2OTBDPS
Scheme 3. Synthesis of fragment B. Reagents and conditions: (a)
BnBr, K2CO3, DMF; (b) LiAlH4, THF, 91% in two steps; (c) MsCl,
Et3N, CH2Cl2, 0 °C; (d) LiAlH4, THF, 60 °C, 74% in two steps; (e)
SO2Cl2, CHCl3, 0 °C, 88%; (f) H2, 10% Pd–C, EtOAc, 90%.
BnO
CHO
OTBDPS
e, f, g
the benzyloxy anion. Among several attempts, relatively
acidic conditions, such as HF–Py, caused decomposition
of 14.
OBn
8
Scheme 2. Synthesis of fragment A. Reagents and conditions: (a)
n-BuLi, )78 °C; prenyl bromide, DME, 0 °C, 78%; (b) n-BuLi, )78 °C;
ClCO2Me, DME, 0 °C, 62%; (c) LiAlH4, THF, 86%; (d) TBDPSCl,
Imid., DMF, 99%; (e) MeI, 40 °C; (f) NaBH4, MeOH, THF; (g) 60%
AcOH, THF, 69% in three steps.
Accordingly, the TBDPS group of 13 was removed in
advance (Scheme 5). Subsequent IBX-oxidation of 17
provided the desired benzophenone 18 in 53% yield,
without undesired cleavage. Removal of the MOM
groups under acidic conditions gave 19. Whereas the
hydrogen transfer method provided a complex mixture,
the Lewis acid conditions employing BBr3 gave SB87-Cl
1 successfully. In the next stage, we attempted synthesis
of pestalone 2, carrying the asymmetric property at the
chlorinated aromatic residue, derived from fragment B.
Monomethylation of 19 led to the desired compound 20,
which on deprotection with BBr3 afforded 2. The spec-
troscopic data of the synthetic 1 and 2, was identical
with the reported data.1;2
corresponding benzyl ester was reduced to give alcohol
9. Mesylation, followed by reduction provided 10. After
dichlorination and removal of the benzyl groups, 11 was
converted by the reported procedure3;6 into bromide 12.
With both fragments in hand, our attention was focused
on the critical coupling reaction of 8 with 12 (Scheme 4).
The bromine–lithium exchange reaction of 12, followed
by coupling with 8 gave the desired product 137 in
quantitative yield. Subsequent IBX oxidation afforded
the nona-substituted benzophenone 14. Unexpectedly,
removal of the TBDPS group under TBAF conditions
caused benzophenone cleavage, leading to 15 and 16,
probably by the intramolecular nucleophilic attack of
In conclusion, the first total synthesis of SB87-Cl 1 and
pestalone 2 has been accomplished, employing the
common synthetic precursor. These results will contrib-
ute to investigation of the structure–activity relationship
and creation of biologically more potent substances.

D. Iijima et al. / Tetrahedron Letters 45 (2004) 5469–5471
5471
Acknowledgements
X
OMOM
Cl
a
This work was supported by Grant-in-Aid for the 21st
Century COE program ‘Keio Life Conjugate Chemis-
try’, as well as Scientific Research C from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan.
BnO
8 + 12
MOMO
BnO OTBDPS
Cl
13 X = H, OH
14 X = O
b
References and notes
O
OMOM
Cl
c
BnO
1. Wachi, Y.; Yamashita, T.; Komatsu, K.; Yoshida, S. JP
Patent JKXXAF JP 07061950 A2 19950307, 1995.
2. Cueto, M.; Jensen, P. R.; Kauffman, C.; Fenical, W.;
Lobkovsky, E.; Clardy, J. J. Nat. Prod. 2001, 64, 1444–
1446.
BnO
O
Cl
MOMO
3. Kaiser, F.; Schmalz, H.-G. Tetrahedron 2003, 59, 7345–
7355.
O
OMOM
Cl
BnO
4. Kennedy, M.; Moody, C. J.; Rees, C. W.; Vaquero, J. J.
J. Chem. Soc., Perkin Trans. 1 1987, 6, 1395–1398.
5. Frey, L. F.; Tillyer, R. D.; Caille, A.-S.; Tschaen, D. M.;
Dolling, U.-H.; Grabowski, E. J. J.; Reider, P. J. J. Org.
Chem. 1998, 63, 3120–3124.
+
O
MOMO
OBn
Cl
15
16
6. Katoh, T.; Ohmori, O.; Iwasaki, K.; Inoue, M. Tetrahedron
2002, 58, 1289–1299.
Scheme 4. Coupling reaction of fragment A with B. Reagents and
conditions: (a) n-BuLi, THF, )78 °C, 99% based on 8; (b) IBX,
DMSO, toluene, 69%; (c) TBAF, THF, 40%.
7. The coupling procedure: To a solution of 12 (0.14 g,
0.38 mmol) in dry THF (2.5 mL) was added n-BuLi in
hexane (1.6 M, 0.19 mL, 0.30 mmol) at )78 °C. After
15 min, a solution of 8 (50 mg, 76 lmol) in dry THF
(0.7 mL) was added to the resulting white suspension at
)78 °C. The mixture was allowed to warm up to 0 °C for
3 h. Usual work-up gave 13 (71mg, 99%, based on 8) as a
X1
OMOM
Cl
colorless oil; IR (film) 3388, 1587 cmÀ1
;
1H NMR
BnO
a
13
(400 MHz, CDCl3) d 0.97 (9H, s), 1.45 (3H, s), 1.52 (3H,
s), 2.47 (3H, s), 3.24 (2H, br), 3.43 (6H, s), 4.45–4.47 (3H,
complex), 4.52 (1H, d, J ¼ 12:0 Hz), 4.63 (1H, d,
J ¼ 12:0 Hz), 4.84 (1H, d, J ¼ 4:4 Hz), 4.95 (1H, d,
J ¼ 12:6 Hz), 4.99 (1H, d, J ¼ 12:6 Hz), 5.22 (1H,
d, J ¼ 11:4 Hz), 5.29 (1H, d, J ¼ 11:4 Hz), 5.73 (1H, d,
J ¼ 2:4 Hz), 6.32 (1H, s), 6.75 (1H, d, J ¼ 2:4 Hz), 6.91–
6.94 (2H, complex), 7.16–7.36 (14H, complex), 7.50–7.52
(2H, complex), 7.62–7.65 (2H, complex); 13C NMR
(100 MHz, CDCl3) d 17.9, 18.6, 19.2, 25.3, 25.4, 26.8,
57.7, 58.3, 69.3, 69.9, 70.2, 96.9, 99.7, 119.5, 121.9, 123.2,
125.6, 127.0, 127.0, 127.1, 127.4, 127.5, 127.6, 128.2, 128.3,
129.3, 129.4, 130.6, 132.0, 133.0, 133.4, 135.6, 135.6, 135.7,
136.9, 137.1, 143.2, 150.4, 155.7, 156.8; HRFABMS calcd
for C54H60O8Cl2SiNa ([M+Na]þ) 957.3332, found
957.3348.
MOMO
BnO X2
Cl
17 X1 = X2 = H, OH
18 X1 = X2 = O
b
O
OH
Cl
c
Cl
BnO
d
1
CHO HO
BnO
19
e
O
OH
BnO
Cl
f
2
CHO MeO
BnO
Cl
20
Scheme 5. Synthesis of SB87-Cl 1 and pestalone 2. Reagents and
conditions: (a) TBAF, THF, quant; (b) IBX, DMSO, toluene, 53%; (c)
6 M HCl, THF, quant; (d) BBr3, CH2Cl2, )78 °C, 73%; (e) MeI,
K2CO3, acetone, 40 °C, quant; (f) BBr3, CH2Cl2, )78 °C, 56%.