Studies toward the total synthesis of irumamycin: stereoselective preparation of the C(15)-C(27) segment via two-directional chain synthesis

Article abstract of DOI:10.1016/j.tetlet.2006.11.079

The basic structure of the C(15)-C(27) part of irumamycin (1) was synthesized. Stereoselective assembly of C16, 17, 22, and an extra C21 stereocenter was achieved by two-directional Brown's asymmetric allyl boration. Group selective PMP acetal formation and oxidative cleavage of vinyl group facilitated the differentiation of the ends of a two-directionally synthesized chain.

Full text of DOI:10.1016/j.tetlet.2006.11.079

Tetrahedron Letters 48 (2007) 413–416
Studies toward the total synthesis of irumamycin:
stereoselective preparation of the C(15)–C(27) segment via
two-directional chain synthesis
Tomoyasu Hirose, Toshiaki Sunazuka, Daisuke Yamamoto, Mutsumi Mouri,
ꢀ
Yoshiaki Hagiwara, Takanori Matsumaru, Eisuke Kaji and Satoshi Omura*
The Kitasato Institute and Kitasato Institute for Life Sciences and Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane,
Minato-ku, Tokyo 108-8642, Japan
Received 17 October 2006; revised 6 November 2006; accepted 10 November 2006
Available online 1 December 2006
Abstract—The basic structure of the C(15)–C(27) part of irumamycin (1) was synthesized. Stereoselective assembly of C16, 17, 22,
and an extra C21 stereocenter was achieved by two-directional Brown’s asymmetric allyl boration. Group selective PMP acetal for-
mation and oxidative cleavage of vinyl group facilitated the differentiation of the ends of a two-directionally synthesized chain.
ꢀ 2006 Elsevier Ltd. All rights reserved.
In 1982, we reported the isolation and determination of
the planar structure of a new 20-membered macrolide,
irumamycin (1) (Fig. 1), isolated from a culture broth
of Streptomyces subflavus subsp., Irumaensis nov. subsp.
AM-3603.1,2 Irumamycin belongs to a group of macro-
lide antibiotics that include venturicidin,3 concanamy-
cin,4 oligomycin,5 and cytovaricin,6 and exhibits high
activity against phytopathogenic fungi.1
total synthesis and determination of the aglycone of ven-
turicidin A and B as a related natural product to 1.8 The
absolute configuration of 1, however, still remained
undefined. Despite the potent physiological activity
and attractive structure of 1, only three publications
have addressed the matter of a reliable protocol toward
the production of 1.7,8 Here, we describe the efficient
preparation of the C(15)–C(27) segment (2) of 1 via
two-directional chain synthesis.
In 1988, Akita et al. reported determination of the abso-
lute structure of the C(16)–C(22) component of iruma-
mycin by enantioselective synthesis of the C(16)–C(22)
fragment and comparison with the C(16)–C(22) degra-
dation product from 1.7 In 1990, they accomplished
We envisioned a strategy toward the total synthesis of 1
to entail a ring-closing olefin metathesis reaction to con-
nect between the C(14) and C(15) vinyl elements, after
equipping the ester component to connect the C(1)–
C(14) and C(15)–C(27) segments of 1. We also planned
the epoxidation of the C(23,24) trisubstituted olefin for a
late stage of the total synthesis. With this plan in mind,
we designed compound (2) as an advanced C(15)–C(27)
subtarget for 1. Retrosynthetic strategy for 2, as shown
in Scheme 1, involves disconnections between C(23) and
C(24) leading to the aldehyde (3), with suitable protec-
tion on OH groups, which can be prepared from the
pseudo C2 symmetric chain (4). Fragment 4 was
designed to be applied via a two-directional chain syn-
thetic strategy9 by the use of Brown’s asymmetric allyl
boration10 of dialdehyde (5). Therefore, the additional
hydroxyl group on C(21) was required to express the
C2 symmetric frame in fragment (4). A similar strategy
was used in the synthesis of FK50611 and streptovaricin
O
O
HO
21
O
O
27
23
15
O
OH
O
O
NH2
O
1
O
OH
Irumamycin (1)
Figure 1. Structure of irumamycin (1).
*
Corresponding author. Tel.: +81 3 5791 6101; fax: +81 3 5791
6380; e-mail: omura-s@kitasato.or.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.079

414
T. Hirose et al. / Tetrahedron Letters 48 (2007) 413–416
Irumamycin (1)
27
15
TIPSO
O
O-(p-MeO)Bz
C(15)–C(27) segment (2)
1) PMP acetal formation
(C17-C19)
additional
OH group
2) Dehydroxylation
(C21-OH)
17
19
3) Oxidative cleavage
(C23-vinyl)
CHO
21
23
OH
OH
O-(p-MeO)Bz
TIPSO
OPMB
3
Pseudo C2-symmetric chain (4)
Two-directional
stereoselective
allylation
OTBS
OHC
CHO
R B
B R
OHC
R
R
OPMB
5
6
Scheme 1. Synthetic strategy of C(15)–C(27) segment (2) of 1.
A.12 In the case of streptovaricin A, the group selective
modification of benzylidene acetal facilitated the differ-
entiation of the diastereotopic termini.12
afford 10 in 83% yield for two steps. The PMP acetal
(10) was then converted to PMB ether at C(19) by reduc-
tive cleavage, followed by deprotection of TBS that gave
diol (11) in 91% yield for two steps. We then converted 11
to the key dialdehyde substrate to allow the two-direc-
tional reaction to proceed. However, the 1H NMR spec-
trum of dialdehyde (5), after quenching with water,
indicated an indeterminate complex mixture. We sus-
pected that this complexity was caused by the equilib-
rium between the dialdehyde and cyclic hydrated
products. Therefore, two-directional allyl boration was
The synthesis of 2 began with chiral aldehyde (6), which
was easily prepared from methyl (R)-(+)-3-hydroxy-2-
methylpropionate (7)13 (Scheme 2). Evans aldol conden-
sation with oxazolidinone (8) furnished the aldol product
(9) in 91% yield for two steps with >20:1 diastereoselec-
tivity. Subsequently, the aldol adduct was reduced with
LiBH4 followed by PMP acetal formation of 1,3-diol to
Bn
O
N
Bn
1) LiBH4, THF
O
O
Ref. 13
8
MeOH, 0 °C (95%)
R
OH
OTBS
19
O
N
OTBS
MeO2C
OHC
BEt3, TfOH,
2) PMPCH(OMe)2,
PPTS, CH2Cl2, rt (87%)
i-Pr2NEt, CH2Cl2, 0 °C
O
OH
O
91%, d.r. > 20 : 1
7
6
(2 steps from alcohol of 6)
9
1) DIBAL-H,
(COCl)2 (6 eq)
DMSO (12 eq)
CH2Cl2, 0 °C
quenched with H2O
OTBS
19
HO
OH
Et3N (20 eq),
–78 °C
2) TBAF, THF, rt
91% for 2 steps
OHC
CHO
O
O
OPMB
OPMB
PMP
5
11
10
OPMB
B((–)-Ipc)2
+H2O
–H2O
OHC
CHO
OPMB
21
23
15
HO
O
OH
, then NaBO3•4H2O,
sat. aq. NaHCO3, rt
OH
OH
OPMB
Pseudo C2 symmetric chain (4)
(–)-Ipc =
Scheme 2. Attemption to prepare pseudo C2 symmetric chain (4).

T. Hirose et al. / Tetrahedron Letters 48 (2007) 413–416
415
attempted with the crude complex mixture (5), but no de-
sired product was observed.
the two-directionally synthesized chain was confirmed
by single-crystal X-ray analysis of this diol.17 Turning
next to the preparation of C(21) dehydroxylated sub-
strate (16), initial efforts involved treatment of a mixture
of 14 and 15 with LiAlH4 in THF, but no desired prod-
uct was observed. Next, we applied Schlesinger’s mixed
hydride reagent18 for this dehydroxylation. In this in-
stance, reaction of 14 and 15 with LiAlH4:AlCl3 (1:4)
complex in diethyl ether furnished a 65% of C(21) meth-
ylene compound, which was converted to PMP acetal
(16) by the use of PMPCH(OMe)2 with PPTS in 99%
yield. Oxidation of the PMP acetal (16) with DDQ
and H2O afforded C(19)-O-(p-MeO)Bz ester as a single
regioisomer in 99% yield. The protection of C(17)–OH
with TIPSOTf gave 17 in 98% yield (based on the recov-
ery of SM). The group selective oxidative cleavage was
carried out by applying the Sharpless’s dihydroxylation
condition with (DHQ)2PYR19 to form diol (18) in 66%
yield20 and a small amount of undesired tetraol product.
The diol (18) was treated with NaIO4, which was
directly coupled with suitable phosphonate via an
HWE reaction to provide C(15)–C(27) segment (2)21 in
88% yield for two steps.
This observation prompted us to postulate that the two-
directional allyl boration may be sequentially carried
out after Swern oxidation without any preparatory pro-
cesses to circumvent the hydration problem of 5. This
action gave us the desired product (4) in 88% yield with
excellent stereoselectivity through oxidation, allyl bora-
tion, and oxidative hydrolysis14,15 (Scheme 3). Accord-
˚
ingly, 4 was treated with DDQ and MS 4 A to afford
more thermodynamically stable PMP acetal in 72% yield
as a single regioisomer.16 The group selective acetal for-
mation between C(17) and C(19) facilitated differentia-
tion of the ends of a two-directionally synthesized
chain. Acetal (12) was then converted into metha-
nesulfonyl ester (13) in 66% yield, which was reacted
with DDQ and H2O to form the mono C(17) or
C(19)-O-(p-MeO)Bz ester as an inseparable mixture.
The mixture was treated with DIBAL-H to convert diol,
which was formed in crystals as the monohydrate com-
plex by slow evaporation from the wet-MeOH and
CHCl3 solvent system. The relative stereochemistry of
1) (COCl)2 (6 eq), DMSO (12 eq),
DDQ
MS-4Å
17
Me+O
HO
Et3N (20 eq), CH2Cl2, –78 °C
11
O
21
23
CH2Cl2, rt
15
B((–)-Ipc)2
, then
21
OH
OH
OPMB
Pseudo C2 symmetric chain (4)
72%
–78 °C
, then NaBO3•4H2O,
OH
//
sat. aq. NaHCO3, rt
single isomer
88%
MsCl,
DDQ,
H2O
17
19
O
17
19
Et3N
CH2Cl2, rt
99%
CH2Cl2, rt
66%
O
OH
O
O
OMs
OR1 OR2 OMs
R1 = (p-MeO)Bz, R2 = H; 14
R1 = H, R2 = (p-MeO)Bz; 15
as mixture of 14 and 15
6.6
12
..
PMP
PMP
1
single regioisomer
13
DIBAL-H,
CH2Cl2, –78 °C
O
O
O
63%
OH OH OMs
diol
O
S
H
O
O
2
ORTEP of diol
1) LiAlH4, AlCl3,
Et2O, rt (65%)
1) DDQ, H2O,
CH2Cl2, rt (99%)
21
14 and 15
2) PMPCH(OMe)2,
PPTS, CH2Cl2, rt (99%)
2) TIPSOTf, 2,6-lutidine
CH2Cl2, rt (45%; 98%
based on recovered SM)
O
O
TIPSO
O(p-MeO)Bz
17
PMP
16
K2OsO4•H2O,
1) aq. NaIO4,
THF/MeOH, rt
K3Fe(CN)6, K2CO3
27
15
OH
OH
(DHQ)2PYR, tBuOH/H2O, 0 °C
2) NaH
TIPSO
O(p-MeO)Bz
TIPSO
O(p-MeO)Bz
O
66%
(EtO)2(O)P
O
18
C(15)-C(27) segment (2)
THF, rt
88% for 2 steps
Scheme 3. Completion of the synthesis of C(15)–C(27) segment.

416
T. Hirose et al. / Tetrahedron Letters 48 (2007) 413–416
CH2Cl2 (68 mL) was added to the reaction mixture at
À78 ꢁC and stirred for 1 h. Then, Et3N (179 mL, 12.0 mol)
was added to the reaction mixture, and the resulting
mixture was transformed into a solution of freshly
In conclusion, the C(15)–C(27) segment (2) was synthe-
sized from aldehyde (6), prepared from commercially
available 7. The pseudo C2 symmetric intermediate (4)
was designed to allow two-directional Brown’s allyl
boration. In general, most applications of the two-direc-
tional strategy require that the ends of the nascent chain
be differentiated. We overcame this problem through
adaptations of group selective PMP cyclic acetal forma-
tion and Sharpless’s dihydroxylation. Further studies
toward the total synthesis of 1 are now in progress.
10
prepared MeOB((À)-Ipc)2 (100 g, 0.316 mol) in THF
(316 mL) via a funnel under argon atmosphere and stirred
for 10 min. The reaction was then quenched with satd aq
NaHCO3 (110 mL). To a crude solution was added
NaBO3Æ4H2O (143 mg, 644 mmol), stirred for 10 h and
then extracted with Et2O (500 mL · 3). The combined
organic layers were dried over Na2SO4, filtered, and
concentrated. The product was purified by flash chroma-
tography (hexane/EtOAc = 10:1) to afford 4 (21.3 g, 88%)
as a colorless oil; 1H NMR (400 MHz, CDCl3) d: 7.24
(2H, d, J = 7.3 Hz), 6.83 (2H, d, J = 7.3 Hz), 5.88–5.64
(2H, complex m), 5.20–5.05 (4H, complex m), 4.64, 4.57
(each 1H, d, J = 10.2 Hz), 3.79 (3H, s), 3.31 (1H, dd,
J = 5.4, 2.2 Hz), 2.35–2.24 (2H, m), 2.08–2.01 (2H, m),
1.06–0.91 (12H, m).
Acknowledgments
This work was supported by a Grant from the 21st
Century COE Program, Ministry of Education, Culture,
Sports, Science and Technology, and the Kato Memo-
rial Bioscience Foundation. We also thank Ms. A.
Nakagawa, Ms. C. Sakabe, Ms. N. Sato, and Ms. Y.
Kawauchi for the various instrumental analyses.
16. 1H NMR (400 MHz, CDCl3) analysis of 12.
H
H
17
O
References and notes
H
PMP
O
19
H
ꢀ
1. Omura, S.; Tanaka, Y.; Nakagawa, A.; Iwai, Y.; Inoue,
H
H
H
8.5%
M.; Tanaka, H. J. Antibiot. 1982, 35, 256.
ꢀ
H
2. Omura, S.; Nakagawa, A.; Tanaka, Y. J. Org. Chem.
12
OH
9.0%
1982, 47, 5413.
3. (a) Brufani, M.; Keller-Schierlein, W.; Lo¨ffler, W.; Man-
sperger, I.; Za¨hner, H. Helv. Chim. Acta 1968, 51, 1293;
(b) Brufani, M.; Cellai, L.; Musu, C.; Keller-Schierlein, W.
Helv. Chim. Acta 1972, 55, 2329.
4. (a) Kinashi, H.; Someno, K.; Sakaguchi, K.; Higashijima,
T.; Miyazawa, T. Tetrahedron Lett. 1981, 22, 3857; (b)
Kinashi, H.; Someno, K.; Sakaguchi, K.; Higashijima, T.;
Miyazawa, T. Tetrahedron Lett. 1981, 22, 3861.
5. (a) Von Glehn, M.; Norrestam, R.; Kierkegaard, P.;
Maron, L.; Ernster, L. FEBS Lett. 1982, 20, 267; (b)
Arnoux, B.; Staron, T. J. Chem. Soc., Chem. Commun.
1978, 318.
6. Kihara, T.; Kusakabe, H.; Nakamura, G.; Sakurai, T.;
Isono, K. J. Antibiot. 1981, 34, 1074.
7. Akita, H.; Yamada, H.; Matsukura, H.; Nakata, T.; Oishi,
T. Tetrahedron Lett. 1988, 29, 6449.
8. (a) Akita, H.; Yamada, H.; Matsukura, H.; Nakata, T.;
Oishi, T. Tetrahedron Lett. 1990, 31, 1731; (b) Akita, H.;
Yamada, H.; Matsukura, H.; Nakata, T.; Oishi, T.
Tetrahedron Lett. 1990, 31, 1735.
9. Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9.
10. Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
11. (a) Schreiber, S. L.; Sammakia, T.; Uehling, D. E. J. Org.
Chem. 1989, 54, 15; (b) Nakatsuka, M.; Ragan, J. A.;
Smmakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S.
L. J Am. Chem. Soc. 1990, 112, 5583; (c) Villalobos, A.;
Danishefsky, S. J. J. Org. Chem. 1990, 55, 2776.
12. (a) Schreiber, S. L.; Wang, Z.; Schulte, G. Tetrahedron
Lett. 1988, 29, 4085; (b) Wang, Z.; Schreiber, S. L.
Tetrahedron Lett. 1990, 31, 31.
NOE
17. Crystal data for diol: C16H30O5S, MW 334.47 was
obtained as clear colorless crystals, space group P21,
˚
˚
˚
a = 8.365(1) A, b = 7.817(2) A, c = 15.379(3) A, Z = 2,
Dcalcd = 1.104 g/cm3, No. of observations (I > 0.00r(I))
1470; R 0.087; Rw 0.198. Crystallographic data of diol
have been deposited with the Cambridge Crystallographic
Data Centre as Supplementary Publication Number
CCDC 622750. Copies of the data can be obtained, free
of charge, on application to CDCC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0) 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
18. (a) Finholt, A. E.; Bond, A. C.; Schlesinger, H. I., Jr. J.
Am. Chem. Soc. 1947, 69, 1199; (b) Ashby, E. C.; Prather,
J. J. Am. Chem. Soc. 1966, 88, 729.
19. (a) Becker, H.; King, S. B.; Taniguchi, M.; Vanhessche, K.
P. M.; Sharpless, K. B. J. Org. Chem. 1995, 60, 3940;
(b) Crispino, G. A.; Jeong, K. S.; Kolb, H. C.; Wang, Z.
M.; Xu, D.; Sharpless, K. B. J. Org. Chem. 1993, 58, 3785.
20. Group selective dihydroxylation of 17 using asymmetric
catalysts.
K2OsO4•2H2O
K3Fe(CN)6, K2CO3,
OH
OH
TIPSO
O
PMP
tBuOH/H2O(1/1), 0 ºC TIPSO
O
PMP
17
18
O
O
Entry
Catalysts
Yields
1
(DHQD)2PHAL (AD-mi-β)
No Reaction
2
3
4
(DHQ)2PHAL (AD-mi-α)
(DHQ)2AQN
48%
13. Chandrasekhar, S.; Reddy, C. R. Tetrahedron: Asymmetry
2002, 13, 261.
14. Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org.
Chem. 1989, 54, 5930.
No Reaction
66%
(DHQ)2PYR
15. Experimental procedure of preparation of (3S,4S,5R,
7R,8S,9S)-6-(4-methoxybenzyloxy)-3,5,7,9-tetramethyl-
1,10-undecadiene 4,8-diol (4): To a solution of (COCl)2
(34.3 mL, 0.386 mol) in CH2Cl2 was added DMSO
(56.7 mL, 0.727 mol) over 30 min at À78 ꢁC. After stirring
for 30 min, a solution of diol 11 (17.0 g, 64.4 mmol) in
21. Compound C(15)–C(27) segment (2): 1H NMR (270 MHz,
CDCl3) d: 7.99 (2H, d, J = 8.6 Hz), 6.92 (2H, d,
J = 8.6 Hz), 6.36 (1H, m), 5.86 (1H, ddd, J = 17.2, 10.2,
6.9 Hz), 5.06 (2H, complex m), 4.97 (1H, m), 3.87 (3H, s),
3.74 (1H, m), 2.70–2.49 (4H, m), 2.11–1.77 (5H, m), 1.77
(3H, s), 1.48–1.19 (2H, m), 1.13–0.90 (33H, complex m).