Synthesis of the C15-C27 portion of venturicidins: A formal total synthesis of venturicidin X

Article abstract of DOI:10.1016/S0040-4039(01)00518-4

The C15-C27 portion of venturicidin X was prepared using substitution reactions of alkyl trifluoromethanesulfonates with a vinylmetal compound followed by homogeneous hydrogenation. Together with our previous synthesis of the C1-C14 portion of venturicidin X, a formal total synthesis of venturicidin X was completed.

Full text of DOI:10.1016/S0040-4039(01)00518-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3607–3611
Synthesis of the C15–C27 portion of venturicidins: a formal total
synthesis of venturicidin X
Keiji Tsunashima, Mitsuaki Ide, Hiroshi Kadoi, Aya Hirayama and Masaya Nakata*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
Received 1 March 2001; accepted 23 March 2001
Abstract—The C15–C27 portion of venturicidin X was prepared using substitution reactions of alkyl trifluoromethanesulfonates
with a vinylmetal compound followed by homogeneous hydrogenation. Together with our previous synthesis of the C1–C14
portion of venturicidin X, a formal total synthesis of venturicidin X was completed. © 2001 Elsevier Science Ltd. All rights
reserved.
The 20-membered macrolide antibiotics, venturicidins
A and B, were isolated from several Streptomyces and
their structures were elucidated by chemical degrada-
tions, spectroscopic investigations, and an X-ray crys-
tallographic analysis.1 In addition, venturicidin X, the
aglycone of the venturicidins, was also isolated from
Streptomyces.2 In 1990, Akita, Oishi, and co-workers
succeeded in synthesizing venturicidin X.3 We have
already reported the synthesis of the C1–C14 portion 1
(the bottom half) of venturicidin X (Fig. 1).4 We now
report in this letter the synthesis of the C15–C27 por-
tion 2 (the upper half) of venturicidin X.5,6 These two
portions, 1 and 2, are the intermediates of the Akita
and Oishi synthesis of venturicidin X;3 therefore, a
formal total synthesis was completed.
During the course of our synthetic studies of macrolide
antibiotics,7 we developed the two-stage coupling pro-
cess which consists of the addition reaction of chiral
vinyllithium compounds to a-methyl-substituted alde-
hydes (e.g. A+B“C, Scheme 1) followed by the homo-
geneous hydrogenation of the exo-methylene group in
27
27
Me Me Me Me Me Me
Me Me Me Me Me Me
14
RO
19
H
23
25
19
15
15
17
21
O
O
OH
O
OH
O
O
OTBS
Me
H
1
Me
Me
O
TBS = t-BuMe2Si-
2
7
3
OH
P(O)(OMe)2
14
Me
O
Venturicidin B:
Venturicidin X
(aglycone of
venturicidins):
Venturicidin A:
R =
R =
1
OH
OH
Me
COOH
HO
Me
H2NCOO
Me
O
R = H
7
3
H
OMe
O
O
Me
1
Figure 1.
Keywords: venturicidins; two-stage coupling process; substitution; hydrogenation.
* Corresponding author. Tel.: +81-45-566-1577; fax: +81-45-566-1551; e-mail: msynktxa@applc.keio.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00518-4

3608
K. Tsunashima et al. / Tetrahedron Letters 42 (2001) 3607–3611
Me
Me
Me
Me Me Me
hydrogenation
addition
CHO
OP3
OP3 OH
OP1
OP3 OH
OP1
OP2
OP2
B
C
D
Me
P1 ~ P3 = protecting groups
M = metal
M
deoxygenation
OP2
OP1
Le = leaving group
A
Me
Me
Me
Me Me Me
hydrogenation
substitution
OP2
OP1
OP3 Le
OP3
OP3
OP1
OP2
F
G
E
Scheme 1.
OH
OH Me
Me
O
Me
Ph
a, b
ref 10
c
Me
CO2Et
Me
I
Me
OH
O
O
OH
O
O
3
Ph
4
5
,
Scheme 2. Reagents and conditions: (a) PhCH(OMe)2, CSA, DMF, rt, 1 h, 80%; (b) PCC, molecular sieves 3 A powder, CH2Cl2,
rt, 1 h, 99%; (c) NH2NH2·H2O, Et3N, EtOH, 90°C, 0.5 h, then I2, tetramethylguanidine, toluene, 0°C, 1 h, 63%.
the major Cram (syn) type of addition products with
Wilkinson’s catalyst (e.g. C“D, Scheme 1). In order to
broaden the applicability of this two-stage coupling
process, we realized the synthesis of the upper half of
venturicidin X, which has the different protecting
groups in 2, starting from B (corresponding to the
C15–C17 portion) by the consecutive coupling with A
(corresponding to both the C18–C21 and C22–C25
portions) followed by a deoxygenation process (e.g.
D“E, Scheme 1).8 However, if the vinyllithium or
vinylmetal compounds A react with alkyl halides or
sulfonates F in an SN2 manner,9 the upper half of
venturicidin X can be more directly obtained without
the deoxygenation step (e.g. A+F“G“E, Scheme 1).
We describe here the success of this strategy.
however, no coupling product was obtained at −78°C
or decomposition occurred when the mixture was grad-
ually warmed to rt. We next examined several additives
(Bu2Mg,15 Et2Zn, ZnCl2, MgBr2·OEt2, CuI, and CuCN
for transmetallation and HMPA, TMEDA, and N,N%-
dimethylpropyleneurea (DMPU) for co-solvent). We
finally found the following procedure to be the best.
After lithiation as described above, 1.0 equiv. of Et2Zn
in hexane was added and the mixture was warmed to
−45°C. To this were added 6.0 equiv. of DMPU and
16
0.08 equiv. of Li2CuCl4 in THF; the mixture was then
warmed to 0°C and to this was added 1.5 equiv. of 9 in
ether. After 3 h at 0°C, usual work-up gave the desired
coupling product 10 in 60% isolated yield.17 This com-
bination of reagents, vinyllithium, Et2Zn, and copper,
is, to the best of our knowledge, the first example to be
used in the SN2 type coupling reaction.16,18–20
Vinyl iodide 5, the precursor of the vinylmetal com-
pound, was prepared as shown in Scheme 2. Triol 3,
which had been prepared from ethyl (S)-(−)-lactate by
a literature procedure,10 was selectively protected as its
benzylidene acetal and the resulting alcohol was oxi-
dized with PCC to give methyl ketone 4.11 This was
converted through its hydrazone into vinyl iodide 511
according to the improved procedure of Barton et al.7a
Our next concern was homogeneous hydrogenation. All
compounds used in the homogeneous hydrogenation
stage of our two-stage coupling process7 had a hydroxy
Me
Me
Me
See text.
Me
I
The key coupling reaction was extensively investigated
(Scheme 3). Initially, we examined the coupling reaction
of the vinyllithium compound derived from vinyl iodide
5 with alkyl halides, 611,12 and 7,11,12 and sulfonates,
811,12 and 911,12 (Tf=trifluoromethanesulfonyl). After
lithiation of 5 (in ether)13 with 2.0 equiv. of t-BuLi in
pentane (−78°C, 5 min),14 each solution containing 1
equiv. of 6, 7, 8, and 9 in ether was individually added;
O
O
TrO
O
O
5
10
Ph
Ph
TrO
6: Le = Br 8: Le = OTs
7: Le = I 9: Le = OTf
Le
Scheme 3.

K. Tsunashima et al. / Tetrahedron Letters 42 (2001) 3607–3611
Me Me Me Me Me Me
3609
Me
Me
Ph
b, c
a
d
O
O
TrO
TrO
O
TrO
O
TrO
OBn OTf
12
10
11
Ph
Me
Me
Me Me Me
Me Me Me
Me
f, g
e
OBn
O
O
TrO
OBn
O
O
13
14
Ph
Ph
Me
Me
Me
Me Me Me Me
Me
Me Me Me
i, j, k, l
h
CHO
2
R1 R2
OBn
TrO
OBn
TrO
OBn
OBn
16a: R1 = OH, R2 = H
16b: R1 = H, R2 = OH
15
Scheme 4. Reagents and conditions: (a) H2, [ClRh(Ph3P)3], benzene, rt, 12 h, 84%; (b) DIBAL, toluene, rt, 2 h, 87%; (c) Tf2O,
2,6-lutidine, CH2Cl2, 0°C, 5 min; (d) 5 (1.0 equiv. for 12), t-BuLi, ether, −78°C, 5 min, then Et2Zn, −45°C, then DMPU, Li2CuCl4,
0°C, then 12, ether, 0°C, 3 h, 15% from the primary alcohol; (e) H2, [ClRh(Ph3P)3], benzene, rt, 12 h, 82%; (f) DIBAL, toluene,
rt, 2 h, 79%; (g) DMSO, (COCl)2, CH2Cl2, −78°C, 0.5 h, then Et3N, −78 to 0°C, 0.5 h; (h) EtMgBr, ether, 0°C, 0.5 h, 92%
(16a:16b=6:1); (i) 1% HCl–MeOH, rt, 3 h, 98%; (j) H2, 10% Pd–C, EtOH, rt, 1 h, 82%; (k) 2,2-dimethoxypropane, PPTS, CH2Cl2,
rt, 3 h, 95%; (l) TBSCl, imidazole, CH2Cl2, rt, 1 h, 98%.
group in the allylic position (C, Scheme 1). Although the
precise reaction mechanism has not been clarified, the
hydroxy group might play a key role in the selectivity.21
In the present case (G, Scheme 1), we had no confirma-
tion of the acceptable selectivity. Fortunately, homoge-
neous hydrogenation of the coupling product 10 with
hydrogen and Wilkinson’s catalyst afforded 1111 in 84%
yield as the sole product (Scheme 4). The configuration
of the newly formed methyl-bearing carbon was verified
by 1H NMR analysis of the six-membered acetal H
derived from 11 through the four-step sequence as shown
in Scheme 5. Benzylidene acetal of 11 was selectively
cleaved with DIBAL and the resulting primary alcohol
was converted to the unstable triflate 12. The second key
coupling reaction of 12 with 5 was realized under the
same conditions as described above; however, the yield
of the coupling product 1311 was only 15%.22 Although
this coupling reaction was insufficient, in order to eval-
uate the overall synthetic strategy, it was decided to
investigate the further transformation. Homogeneous
hydrogenation of 13 cleanly proceeded to afford 1411 in
82% yield as the sole product. Reductive cleavage of
benzylidene acetal in 14 with DIBAL and the resulting
primary alcohol was oxidized under the Swern condi-
tions, giving aldehyde 15. Addition of ethylmagnesium
bromide to 15 afforded a 6:1 mixture of the Felkin–Anh
alcohol 16a11 and its epimer 16b11 in 73% combined yield
from 14. The major alcohol 16a was transformed to the
C15–C27 segment 2 through the four-step sequence in
75% overall yield. The obtained synthetic 2 was identical
with the reported one3b,5b based on a spectroscopic
comparison;23 the configurations of the C22 and C25
positions were confirmed at this stage. Together with our
previous synthesis of the C1–C14 portion 1 of venturi-
cidin X,4 a formal total synthesis of venturicidin X was
thus completed.
1) 1:1 HCOOH/ether, r.t., 1 h
2) DMSO, (COCl)2, CH2Cl2,
-78 ˚C, 0.5 h, then Et3N,
-78 to 0 ˚C, 0.5 h
Me Me Me
O
TrO
O
3) 2% HCl-MeOH, r.t., 1 h,
α:β = 3:1
11
Ph
4) Ac2O, DMAP, EtOAc, r.t.,
0.5 h, 39% for 4 steps
Me
Me
Me
H
19
O
H
15
O
OAc
H
H
Me
17
H
Me
H
H
OMe
OMe
NOE: H19 → H18, 5.4% H19 → H17ax, 2.7%
J15,16 = 3.6 Hz, J16,17ax = 13.0 Hz,
J16,17eq = 3.2 Hz, J17ax,17eq = 13.0 Hz,
J17ax,18 = 4.2 Hz, J17eq,18 = 3.2 Hz
Scheme 5.
Although there is still room for improvement in the
coupling reaction described herein, we believe this reac-
tion would be an alternative to the Negishi19 and
Jackson20 cross-coupling reactions.
References
1. (a) Rhodes, A.; Fantes, K. H.; Boothroyd, B.; McGona-
gle, M. P.; Crosse, R. Nature 1961, 192, 952–954; (b)
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C.; Cellai, L.; Keller-Schierlein, W. Experientia 1971, 27,

3610
K. Tsunashima et al. / Tetrahedron Letters 42 (2001) 3607–3611
604–606; (d) Brufani, M.; Cellai, L.; Musu, C.; Keller-
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13. In THF, significant decomposition occurred.
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forsch. 1994, 49b, 977–980.
15. Recently, we described the usefulness of Bu2Mg as an
additive for the dithiane coupling chemistry. See: (a) Ide,
M.; Yasuda, M.; Nakata, M. Synlett 1998, 936–938; (b)
Ide, M.; Nakata, M. Bull. Chem. Soc. Jpn. 1999, 72,
2491–2499; (c) Ide, M.; Nakata, M. J. Synth. Org. Chem.
Jpn. 2000, 58, 857–868.
3. (a) Akita, H.; Yamada, H.; Matsukura, H.; Nakata, T.;
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Oishi, T. Tetrahedron Lett. 1990, 31, 1735–1738.
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66, 3464–3474.
16. (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41,
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Liebigs Ann. 1996, 1717–1724.
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Chichester, 1994; pp. 283–382.
& Sons:
17. Instead of triflate 9, iodide 7 was recovered from the
reaction mixture. This indicates that LiI, which exists in
the reaction mixture, competitively attacks triflate 9. A
separate experiment showed that iodide 7 is less reactive
than triflate 9. In order to prevent this exchange, the
vinyl tributyltin equivalent of 5 was prepared and sub-
jected to the lithiation conditions; however, all efforts
resulted in failure.
18. (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93,
2117–2188; (b) Knochel, P.; Perea, J. J. A.; Jones, P.
Tetrahedron 1998, 54, 8275–8319; (c) Erdik, E. Organo-
zinc Reagents in Organic Synthesis; CRC Press: Boca
Raton, FL, 1996; (d) For recent organozincate chemistry,
see: Uchiyama, M.; Kameda, M.; Mishima, O.;
Yokoyama, N.; Koike, M.; Kondo, Y.; Sakamoto, T. J.
Am. Chem. Soc. 1998, 120, 4934–4946 and references
cited therein.
19. For recent examples of the Negishi palladium-catalyzed
cross-coupling19e of alkyl zinc intermediates with vinyl
iodides and triflates for natural product syntheses, see: (a)
Hu, T.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc.
1999, 121, 9229–9230; (b) Hirashima, S.; Aoyagi, S.;
Kibayashi, C. J. Am. Chem. Soc. 1999, 121, 9873–9874;
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LaMarche, M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823–
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M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D.
R.; Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654–
8664; (e) Negishi, E.; Valente, L. F.; Kobayashi, M. J.
Am. Chem. Soc. 1980, 102, 3298–3299.
20. For recent examples of the Jackson palladium-catalyzed
cross-coupling of amino acid-derived organozinc interme-
diates with vinyl (and aryl) iodides and triflates, see: (a)
Masaki, H.; Mizozoe, T.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Tetrahedron Lett. 2000, 41, 4801–4804;
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Gonza´lez, M.; Jackson, R. F. W. Chem. Commun. 2000,
2423–2424.
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Keay, B. A. Synlett 1996, 135–137.
7. (a) Nakata, M.; Arai, M.; Tomooka, K.; Ohsawa, N.;
Kinoshita, M. Bull. Chem. Soc. Jpn. 1989, 62, 2618–2635;
(b) Nakata, M.; Akiyama, N.; Kamata, J.; Kojima, K.;
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Synth. Org. Chem. Jpn. 1986, 44, 206–218; (d) Nakata,
M.; Tatsuta, K. In Studies in Natural Products Chemistry;
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12, pp. 35–62.
8. (a) Nakata, M. J. Synth. Org. Chem. Jpn. 1989, 47,
1146–1157; (b) Nakata, M.; Kadoi, H.; Nishimura, T.;
Ohashi, J.; Ohsawa, K.; Tatsuta, K.; Kinoshita, M. 65th
National Meeting of the Chemical Society of Japan:
Tokyo, March 1993; Abstr. No. 4H1 47.
9. Recently, similar coupling reactions were reported for the
synthetic studies on natural products. See: (a) Hoye, T.
R.; Tennakoon, M. A. Org. Lett. 2000, 2, 1481–1483; (b)
Kadowaki, C.; Chan, P. W. H.; Kadota, I.; Yamamoto,
Y. Tetrahedron Lett. 2000, 41, 5769–5772.
10. Toshima, K.; Jyojima, T.; Yamaguchi, H.; Noguchi, Y.;
Yoshida, T.; Murase, H.; Nakata, M.; Matsumura, S. J.
Org. Chem. 1997, 62, 3271–3284.
11. Satisfactory analytical data (NMR and IR spectra, ele-
mental analyses and/or HRMS, optical rotations) were
obtained for all new compounds.
12. Compounds 6 and 7 were prepared from the known
alcohol i7a by the literature procedure (Classon, B.; Liu,
Z.; Samuelsson, B. J. Org. Chem. 1988, 53, 6126–6130).
Compounds 8 and 9 were prepared from i7a as shown in
Scheme 6.
Br2, Ph2PCl, imidazole,
6
toluene, r.t., 5 min, 93%
I2, Ph2PCl, imidazole,
Me
7
21. Brown, J. M. Angew. Chem., Int. Ed. Engl. 1987, 26,
190–203.
toluene, r.t., 5 min, 91%
TsCl, Et3N, CH2Cl2,
22. The low yield of 13 was due to not only the inertness of
the iodide equivalent of 12, which was derived from 12
and in-situ contaminated LiI, but also the instability of
12.
TrO
OH
8
9
i
r.t., 18 h, 74%
Tf2O, 2,6-lutidine, CH2Cl2,
23. Compound 2: [h]D24 +33.6 (c 2.09, CHCl3) [lit.,3b [h]2D0
+32.7 (c 2.14, CHCl3). lit.,5b [h]D20 +32.8 (c 2.10, CHCl3)].
IR (neat): 3440, 2960, 2930, 2880, 2860, 1470, 1460, 1380,
0 °C, 5 min, 74%
Scheme 6.

K. Tsunashima et al. / Tetrahedron Letters 42 (2001) 3607–3611
3611
1250, 1220, 1180, 1150, 1100, 1020, 980, 880, 840, 780, and
[after D2O addition, the peaks of 1.59–1.83 (6H, m) and
3.08–3.17 (2H, m) change to those of 1.60–1.83 (5H, m) and
3.12 (2H, dd, J=7.0 and 4.0 Hz), respectively]. 13C NMR
(CDCl3, 75 MHz): l −5.35, 10.53, 12.65, 12.94, 14.67,
16.00, 16.55, 18.34, 23.64, 25.36, 25.96, 32.08, 33.10, 33.46,
33.51, 35.12, 36.19, 37.67, 68.97, 71.21, 79.25, 80.01,
100.14. HRMS (FAB+) calcd for C27H56NaO4Si (M+Na)+:
495.3846. Found: 495.3864.
1
760 cm−1. H NMR (CDCl3, 300 MHz): l 0.04 (6H, s),
0.80–0.95 (18H, m), 0.89 (9H, s), 1.08 (1H, ddd, J=13.2,
9.2, and 4.4 Hz), 1.22 (1H, ddd, J=13.2, 9.8, and 3.0 Hz),
1.30 (3H, s), 1.32 (3H, s), 1.33–1.48 (3H, m), 1.53 (1H, ddd,
J=13.0, 10.0, and 2.8 Hz), 1.59–1.83 (6H, m), 3.08–3.17
(2H, m), 3.36 (1H, dd, J=9.6 and 6.4 Hz), 3.44 (1H, dd,
J=9.6 and 5.8 Hz), 3.63 (1H, ddd, J=8.6, 4.4, and 4.4 Hz)
.
.