Studies directed toward the synthesis of viridenomycin. Route 2: A second generation approach

Article abstract of DOI:10.1016/S0040-4039(01)00701-8

A second generation approach toward the synthesis of viridenomycin is described. Three key fragments of the molecule have been synthesized in stereochemically pure form. Initial studies toward the coupling of these fragments with the aim of assembling the macrocycle are detailed. Final efforts to reach the title compound are documented.

Full text of DOI:10.1016/S0040-4039(01)00701-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4305–4308
Studies directed toward the synthesis of viridenomycin. Route 2:
a second generation approach
Alex G. Waterson, Albert W. Kruger and A. I. Meyers*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523-1872, USA
Received 9 April 2001; accepted 24 April 2001
Abstract—A second generation approach toward the synthesis of viridenomycin is described. Three key fragments of the molecule
have been synthesized in stereochemically pure form. Initial studies toward the coupling of these fragments with the aim of
assembling the macrocycle are detailed. Final efforts to reach the title compound are documented. © 2001 Elsevier Science Ltd.
All rights reserved.
In the preceding paper,1 studies from this laboratory
directed toward the total synthesis of viridenomycin 1,
a macrocyclic antibacterial agent,2 were described. The
key components of the latter strategy were: (1) both
tetraene constructions via Julia coupling3 and palla-
dium cross-coupling, followed by alkyne reduction, and
(2) macrocyclic closure via amide bond formation. In
the course of that work, problems associated with the
Julia coupling were identified. We therefore began an
alternate strategy for the construction of viridenomycin
1 (Scheme 1). The results are described in this letter.4
tetraene (E,E,Z,Z) of 1 via a Stille coupling6 between
the vinyl iodide of 2 and the stannyl triene 4. A lactam
bond linkage was envisioned to complete the macro-
cyclic ring of viridenomycin 1.
The elaborated cyclopentenyl fragment 2 was prepared
via improved modifications of the previously disclosed
route (Scheme 2).7 The point of divergence occurs at
allylic alcohol 5, which was now masked as its benzyl
ether 6. The double bond was dihydroxylated and
converted into the corresponding cyclic sulfate 7,8
which was regioselectively opened with cesium acetate.
The resulting hydroxyl group was protected as a silyl
ether and the acetate moiety was hydrolyzed and con-
verted into the required methyl ether 8. Hydrogenation
to remove the benzyl ethers, Swern oxidation of the
carbinols,9 and Takai olefination10 of the carboxalde-
hyde produced the key vinyl iodide 9. Reaction of the
enolate of ketone 9 with methylcyanoformate followed
In order to circumvent the previously encountered
problems1 with the Julia olefination, this new approach
includes the use of a phosphorous-based olefination
method (i.e. Wittig or Horner–Emmons)5 to construct
the upper tetraene (E,E,E,Z) in 1 (Scheme 1). Also
concerned by the use of a late-stage alkyne reduction,1
we opted to attempt direct installation of the lower
R3P
Ph
Me
O
O
Me
3
Ph
NH
NHBOC
O
O
MeO
MeO
TBSO
HO
O
H3CO
O
I
OR
O
Me
Me
HO
Bu3Sn
2
1, Viridenomycin
4
Scheme 1.
* Corresponding author. E-mail: aimeyers@lamar.colostate.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00701-8

4306
A. G. Waterson et al. / Tetrahedron Letters 42 (2001) 4305–4308
BnO
BnO
MeO
TBSO
HO
BnO
a
e,f,g,h
b,c,d
O
O S
O
OBn
OBn
OBn
OBn
Me
O
Me
Me
Me
5
6
7
8
Me
OMe
O
O
R
MeO
MeO
TBSO
10
O
n,o,p,q
MeO
MeO
TBSO
i,j,k
l,m
MeO
TBSO
O
I
I
Me
Me
I
Me
11, R = CO2Me
12, R = CH2OH
2, R = CHO
9
Scheme 2. Conditions: (a) KH, BnBr, THF, 0°C; (b) OsO4, NMO, acetone/water, −15°C; (c) SOCl2, Et3N, CH2Cl2, 0°C; (d)
NaIO4, RuCl3, CCl4/CH3CN/H2O; (e) 1. CsOAc, DMF, 55°C; 2. H3O+; (f) TBSCl, imidazole, DMF; (g) K2CO3, MeOH, 55%
(seven steps); (h) NaH, MeI, THF; (i) PdꢀC, H2, EtOH; (j) DMSO, Et3N, (COCl)2, CH2Cl2; (k) CrCl2, CHI3, THF, 70% (four
steps); (l) LDA, CNCO2CH3, HMPA, Et2O, −78°C, 64%; (m) MeO2SO2, DBU, DMSO, 75%; (n) LiOH, dioxane/water, 95°C,
75%; (o) 1. 2,4,6-trichloro-benzoyl chloride, Et3N, THF; 2. methylacetoacetate, Et3N, DMAP, HMPA, 84%; (p) DIBALH, THF,
−60°C, 82%; (q) Dess–Martin periodinane, CH2Cl2, 75%.
by methylation of the resulting enol gave ester 10,
which was saponified and activated as a mixed anhy-
dride. Condensation of the latter with methyl acetoac-
etate produced enol ester 11, while DIBALH reduction
to carbinol 12 and Dess–Martin oxidation11 gave the
requisite fragment 2.
in a 30:1 ratio, favoring the desired trans olefin.16
Satisfactory results were also obtained using this ylide
and the model aldehyde 15 (entry g).
The highly substituted vinyl iodide 2 was next coupled
with stannane 4a in quantitative yield to give tetraene
20 with all of the stereochemical integrity preserved
(Scheme 4). Phosphonium salt 21 was prepared from
the reaction of trimethyl phosphine and the previously1
constructed bromide in THF and, due to its hygro-
scopic nature, was immediately deprotonated with n-
BuLi to generate the corresponding ylide. Reaction of
multiple equivalents of the ylide with aldehyde 20 at
−40°C produced the desired bis-tetraene 22 as a 1:1
mixture of olefin isomers, presumably at the newly
formed bond. It is interesting to note that the presence
of the extended conjugation in aldehyde 20 dramati-
cally reduces the reactivity of the carboxaldehyde group
(16–20 h) when compared with model aldehyde 15
(which reacted immediately at −78°C). The slow nature
of the reaction may also be responsible for the poor
E,Z selectivity during the Wittig coupling.
Trienyl fragment 4 was prepared in two variations from
known aldehyde 1312 (Scheme 3). Use of the appropri-
ate Still–Gennari-style phosphonate13 afforded the trans
dienes 14 with greater than 20:1 E:Z ratios. Palladium
coupling with known distannylethylene14 provided the
desired trienes 4.
The use of phosphonate carbanions to establish the E
alkene in the linkage of fragments 2 and 3 was our
original plan. However, use of a phosphonate (entries a
and b, Table 1) resulted in an unfavorable rearrange-
ment in model aldehyde 15, producing only ketone 16.
We felt that a Wittig reagent, which utilizes a classic
ylide, might suppress this rearrangement. Tamura15 has
disclosed that tri-butyl phosphine derived ylides give
excellent trans olefin ratios when using semistabilized
ylides. However, in our hands, reaction of the ylide
derived from a tri-butylphosphonium salt (entries c and
d) with 2-hexenal 17 gave triene 18 in relatively poor
E:Z ratios. Use of the ylide derived from the deproto-
nation of a trimethyl phosphine based salt with n-BuLi
(entry f) gave excellent selectivity, producing triene 19
With 22, containing all the requisite atoms of virideno-
mycin, now in hand, albeit as a mixture of two olefin
isomers, attempts to remove both tert-butyl based pro-
tecting groups in 22 met with abject failure. Various
decomposition products were obtained from a variety
CO2R
a
b
CO2R
I
CHO
I
Bu3Sn
14a, R=t-Bu
14b,R=Me
4a, R=t-Bu
4b,R=Me
13
Scheme 3. (a) (CF3CH2O)2POCH2CO2R, KHMDS, 18-Crown-6, THF, −78°C, 78% (14a), 91% (14b); (b) trans-
Bu3SnCHꢁCHSnBu3, Pd(PPh3)4, THF, 35°C, 61% (4a), 58% (4b).

A. G. Waterson et al. / Tetrahedron Letters 42 (2001) 4305–4308
Table 1. Study of triene construction conditions
4307
O
R
PL3
PL3
R
Base
Ratio
Aldehyde
Product
Entry
R
(E:Z)
KOt-Bu
n-BuLi
KOt-Bu
n-BuLi
KOt-Bu
n-BuLi
-
a
b
c
d
e
f
CH3
CH3
H
PO(OEt)2
PO(OEt)2
PBu3
15
"
16
"
-
2.6:1
2.9:1
3.0:1
30:1
17
"
18
"
H
PBu3
H
PMe3
"
"
H
PMe3
"
"
g
H
PMe3
n-BuLi
15
19
10:1
(90 %)
Key:
O
Me
O
(E,Z)
O
O
O
O
O
Me
O
Me
O
15
18
16
17
19
Me
O
Me
O
O
O
O
MeO
MeO
MeO
TBSO
a
Ot-Bu
Ot-Bu
O
MeO
O
Bu3Sn
O
I
Me
Me
TBSO
2
20
4a
Me
O
Ph
NHBOC
MeO
MeO
TBSO
b
Ot-Bu
O
BrMe3P
O
Ph
NHBOC
Scheme 4. Conditions: (a) PdCl2(CH3CN)2, DMF, 100%; (b) 21, n-BuLi, THF, then 20, −40°C, 80%.
Me
21
22
of known deprotection conditions. The most common
difficulty appeared (NMR) to be acidic hydrolysis of
the rather sensitive enol ester bond. Therefore, we felt
that the macrocycle might be better constructed via a
more convergent strategy, using a moiety such as 28
(Scheme 5), wherein the lactam linkage was already in
place. To this end, ester 4b was saponified and the
resulting acid 23 was activated with PyBOP. To this
OMe
a
OH
R
Bu3Sn
HO
O
Bu3Sn
HO
O
Ph
4b
23
25
c
NH
Bu3Sn
O
b
Ph
Ph
NHBOC
26, R=OH
27, R=Br, OTs
28, R=PMe3Br
24
NH3Cl
Scheme 5. Conditions: (a) LiOH, t-BuOH/water, 95%; (b) HCl, EtOAc, 100%; (c) 23, EtNi–Pr2, PyBOP, CH2Cl2, then 25, 40%.

4308
A. G. Waterson et al. / Tetrahedron Letters 42 (2001) 4305–4308
was added amine salt 25 (prepared from the deprotec-
tion of alcohol 241), resulting in the formation of the
B-ring precursor 26 in 40% yield. The lability of the
allylic alcohol in 26 appeared to be the primary source
of the low conversion, undergoing a number of dis-
placement and/or cyclization side reactions. A variety
of attempts to convert the allylic alcohol into the
corresponding allylic bromide or tosylate, 27 resulted in
the destruction of the molecule. Again, the lability of
the allylic hydroxyl and the presence of the vinyl stan-
nane appear to interfere with further attempts to pre-
pare the requisite ylide in this instance (although
successful ylide formation was achieved with 21).
Antibiot. 1975, 28, 167.
3. (a) Julia, M. Pure Appl. Chem. 1985, 57, 763; (b) Trost,
B. M. Bull. Chem. Soc. Jpn. 1988, 61, 107.
4. All new compounds were fully characterized by optical
rotation, IR, HRMS, and H and 13C NMR.
1
5. (a) Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21,
1; (b) Walker, B. J. In Organophosphorous Reagents in
Organic Synthesis; Cadogen, J. I. G., Ed.; Academic
Press: New York, 1979; p. 155.
6. Farina, V.; Krishnamurty, V.; Scott, W. J. Org. React.
1997, 50, 1.
7. Arrington, M. P.; Meyers, A. I. Chem. Commun. 1999,
1371.
8. (a) Gao, Y.; Sharpless J. Am. Chem. Soc. 1988, 110,
7538; (b) Lohray, B. Synthesis 1992, 1035.
9. Tidwell, T. T. Org. React. 1990, 39, 297.
10. (a) Furstner, A. Chem. Rev. 1999, 99, 991; (b) Takai, K.;
Nitta, K.; Utimoto, K. J. J. Am. Chem. Soc. 1986, 108,
7408.
In conclusion, three key pieces involved in a second
generation strategy aimed at the total synthesis of
viridenomycin have been prepared. In addition, all of
the atoms of viridenomycin have been incorporated,
however, the final closure of the macrocycle and the
completion of the molecule still remains unrealized.17
11. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
12. Marek, I.; Meyer, C.; Normant, J.-F. Org. Synth. 1983,
24, 4405.
Acknowledgements
13. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
14. Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109,
813.
15. Tamura, R.; Saegusa, K.; Kakihana, M.; Oda, D. J. Org.
Chem. 1988, 53, 2723.
The authors are grateful to the National Institute of
Health and National Science Foundation, Merck, and
SmithKline Beecham for support of this work.
16. The increase in selectivity is likely due to the decreased
size of the methyl ligands on the phosphorous. Thus, this
is essentially an enhancement of the effect observed by
Tamura (see Ref. 15).
References
1. Kruger, A. W.; Meyers, A. I. Tetrahedron Lett. 2001, 42,
4301.
2. (a) Nakagawa, M.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1991, 32, 659; (b) Hasegawa, T.;
Kamiya, T.; Henmi, T.; Iwasaki, H.; Yamatodani, S. J.
17. Due to personal considerations, the primary author has
retired and is no longer in a position to continue this
work. However, all spectral data and experimental details
for all compounds described herein are on file with the
senior author.
.