Second-generation synthesis of the polypropionate subunit of callystatin A based on regioselective internal alkyne hydrostannation.

Article abstract of DOI:10.1021/ol026791m

[formula: see text] An improved route to the polypropionate segment of callystatin A is described in which the efficient directed hydrostannation of an internal alkyne and subsequent iodinolysis provides a key vinylic iodide intermediate.

Full text of DOI:10.1021/ol026791m

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3931-3934
Second-Generation Synthesis of the
Polypropionate Subunit of Callystatin A
Based on Regioselective Internal Alkyne
Hydrostannation
James A. Marshall* and Matthew P. Bourbeau
Department of Chemistry, UniVersity of Virginia, P.O. Box 400319, McCormick Road,
CharlottesVille, Virginia 22904-4319
jam5x@Virginia.edu
Received August 26, 2002
ABSTRACT
An improved route to the polypropionate segment of callystatin A is described in which the efficient directed hydrostannation of an internal
alkyne and subsequent iodinolysis provides a key vinylic iodide intermediate.
The marine polyketide callystatin A has generated a great
deal of interest since Kobayashi’s initial report on its structure
and isolation and his ensuing total synthesis.1 Subsequently,
no less than five additional total syntheses were completed.2
Our own efforts were motivated by the reported levels of
cytotoxic activity against several tumor cell lines (IC50
)
10 pg/mL against KB cells and 20 pg/mL against L1210
cells).1 The sequence that we developed was highly conver-
gent and well suited to the production of potentially bioactive
analogues.2e A key feature of our approach to the C12-C22
polypropionate segment was the use of chiral allenyl tin and
zinc reagents to control the relative and absolute stereo-
chemistry (Figure 1).
Recently, we required an additional quantity of callystatin
A for studies on differential cytotoxicity. This need provided
an opportunity to reexamine a segment of our synthesis that
we considered the least satisfactory whereby the homopro-
pargylic alcohol B (itself the product of an allenyl zinc
(1) (a) Kobayashi, M.; Higuchi, K.; Murakami, N.; Tajima, H.; Aoki, S.
Tetrahedron Lett. 1997, 38, 2859. (b) Murakami, N.; Wang, W.; Aoki, M.;
Tsutsui, Y.; Sugimoto, M.; Kobayashi, M. Tetrahedron Lett. 1998, 39, 2349.
(2) (a) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120,
9084. (b) Smith, A. B., III; Brandt, B. M. Org. Lett. 2001, 3, 1685. (c)
Kalesse, M.; Quitschalle, M.; Khandavalli, C. P.; Saeed, A. Org. Lett. 2001,
3, 3107. (d) Marshall, J. A.; Bourbeau, M. P. J. Org. Chem. 2002, 67, 2751.
(e) Vicario, J. L.; Job, A.; Wolberg, M.; Mu¨ller, M.; Enders, D. Org. Lett.
2002, 4, 1023.
Figure 1. Synthesis of the C12-C21 polyketide subunit of
callystatin A.
addition to aldehyde A) was converted to the enyne F by
way of aldehyde D through a somewhat circuitous eight-
10.1021/ol026791m CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/09/2002

step sequence. The use of the alkyne moiety of adduct B as
an aldehyde surrogate for D, though workable, was both
unaesthetic and inefficient, as was the subsequent appendage
of the alkynyl group of F via the Wittig ester product E.
This approach also required that we temporarily protect the
C17 alcohol as a TMS ether and then liberate the alcohol
after an ensuing homologation step. A more integrated
approach would employ the allenylzinc adduct G of aldehyde
A as the precursor to enyne F by way of vinyl iodide H.
This strategy takes direct advantage of the alkyne generated
in the allenyl zinc addition to aldehyde A, and would allow
the C17 alcohol to remain unprotected for the duration of
the synthesis (Figure 2).
ether 5 afforded the vinyl iodide 7 in only 15% yield, and
the derived alcohol 6 yielded an intractable mixture of
products.
As a possible alternative approach to the vinylic iodide
intermediate, we examined the Pd(0)-catalyzed hydrostan-
nation of alkyne 5. Although most investigators have reported
low yields and poor regioselectivities of hydrostannations
involving internal alkynes,5-8 the findings of Benachie et
al.6 on an alkyne closely related to 5 and G prompted our
consideration of the methodology.
Unfortunately, alkyne 5 proved to be quite unreactive
under the reported conditions.6 Starting material was largely
recovered after prolonged reaction times, and none of the
desired adduct 9 could be detected (eq 2). The alcohol 6
proved to be slightly more reactive, but the adduct 10 was
produced in only 20% yield. Following these unpromising
results, we noted a report by Miyake and Yamamoto,7 who
found that Pd(0)-catalyzed hydrostannation of 2-butyn-1-ol
afforded a 15:85 mixture of (E)-3-(tributylstannyl)-2-buten-
1-ol and (E)-2-(tributylstannyl)-2-buten-1-ol, suggestive of
a directing effect by the propargylic OH.8
Figure 2. Proposed new route to the C12-C21 subunit of
callystatin A.
We postulated that the combination of this presumed
directing effect and the presence of a branched alkyl
substituent might conspire to enhance the regioselectivity in
propargylic alcohols such as 11 (eq 3). Should this be the
case, the resulting vinylic hydroxymethyl substituent could
serve as a synthetic equivalent of a vinylic methyl group
following hydrogenolysis of the allylic alcohol.
The conversion of alkyne G to vinyl iodide H would be
most directly achieved by a sequential syn hydrometalation
and iodinolysis. However, we were somewhat concerned
about both the reactivity of an internal alkyne as well as the
regioselectivity of such a hydrometalation. These concerns
prompted us to explore this reaction on a less complicated
system than G. For this study, we prepared the homopro-
pargylic alcohol 6 and silyl ether 5 from hydrocinnamalde-
hyde (1) and the allenylzinc reagent derived from the racemic
butynyl mesylate 2,3 as outlined in eq 1.
The validity of this conjecture was tested on the afore-
mentioned alcohol 11, obtained by formylation of the lithio
derivative of alkyne 4 (eq 3). We also prepared diol 12 and
acetates 13 and 14 as possible substrates. These latter
derivatives were of interest because of a formulated mecha-
nistic pathway for a directed hydrostannation.8
Our initial attention was directed at the hydrozirconation4
of alkyne 5 and subsequent in situ iodinolysis (eq 2). The
results proved to be quite unsatisfactory. The alkynyl TBS
(5) Cf.: Zhang, H.-X.; Guibe´, F.; Balavoine, G. J. Org. Chem. 1990,
55, 1857.
(3) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999, 64, 5201.
(4) (a) Negish, E.-I. In Organometallics in Synthesis; Schlosser, M., Ed.;
2nd ed.; Wiley and Sons, Ltd.: Chichester, UK, 2002; p 934. (b) Buchwald,
S. L.; LaMaire, S. J.; Nielson, R. B.; Watson, B. T.; King, S. M. Tetrahedron
Lett. 1987, 34, 3895. (c) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912.
(6) Benachie, M.; Skrystrup, T.; Khuong-Huu, F. Tetrahedron Lett. 1991,
32, 7535.
(7) Miyake, H.; Yamakura, K. Chem. Lett. 1989, 981.
(8) Rice, M. B.; Whitehead, S. L.; Horvath, C. M.; Muchnij, J. A.;
Maleczka, R. E. Synthesis 2001, 1495.
3932
Org. Lett., Vol. 4, No. 22, 2002

bromide 20 and ensuing treatment with Super Hydride11 was
more successful and afforded the vinylic iodide 22 in
excellent yield.12
Table 1. Hydrostannation of Propargylic Alcohols and
Acetatesa
Pursuant to our intended application of the hydrostannation
hydrogenolysis sequence, a third option was explored
(Scheme 2). Accordingly, the acetoxymethyl stannane 17 was
iodinated and the vinylic iodide 23 subjected to Sonogashira
R1
R2
yield, %
Scheme 2a
H
H
Ac
Ac
TBS (11)
H (12)
TBS (13)
H (14)
62 (15)
65 (16)
83 (17)
89 (18)
a Reaction conditions: (a) Bu3SnH, Pd(Ph3P)2Cl2, THF.
In fact, the catalyzed hydrostannation of propargylic
alcohol 11 gave vinylstannane 15 as the sole adduct (Table
1). Furthermore, the acetate derivative 13 was equally
selective affording adduct 17 in high yield.9 Similarly, diol
12 and monoacetate 14 provided the vinylstannanes 16 and
18 with excellent regioselectivity. The acetate results were
especially encouraging, as we have previously shown that
propargylic acetates such as 14 can be formed directly from
aldehydes and allenylzinc and indium reagents generated in
situ from the mesylate of enantiopure 4-acetoxymethyl-3-
butyn-2-ol.3
Following this satisfactory solution to the hydrostannation
regioselectivity problem, we turned our attention to the issue
of hydrogenolysis. As a first step in this direction, we
attempted the conversion of stannylated allylic alcohol 15
to bromide 21. However, the rather unstable allylic bromide
could be isolated in no greater than 50% yield (Scheme 1).10
a Reaction conditions: (a) I2, THF; (b) TMS acetylene,
Pd(PPH3)2Cl2, CuI, Et3N; (c) NaOH; (d) MsCl, Et3N; (e) LiBr; (f)
LiBEt3H.
coupling13 with TMS acetylene to afford the enyne 24.
Saponification of the acetate proceeded with concomitant
desilylation to yield alcohol 25, which was converted via
mesylate 26 to bromide 27. Hydrogenolysis with Super
Hydride gave rise to enyne 28 in satisfactory overall yield.14
Applying these findings to the callystatin problem, we
effected addition of the allenylzinc reagent derived from
mesylate 30, of 95% enantiomeric purity, to aldehyde 29 to
produce anti adduct 31 (Scheme 3). Pd-catalyzed hydrostan-
Scheme 1
Scheme 3a
An alternative route involving iodinolysis of stannane 15
followed by conversion of the derived iodo alcohol 19 to
(9) Maleczka and co-workers have described hydrostannations of acety-
lenes substituted by (CH2)nOR substituents, where R ) H, Me, or various
silyl groups, and n ) 1-4.8 They also examined the corresponding acetates
where n ) 2-4. Methyl propargyl ether exhibited the highest regioselectivity
(70:30). Propargyl acetate (n ) 1) was not examined because of its “reported
instability under the reaction conditions.” Cf.: Zhang, H. X.; Guibe´, F.;
Balavoine, G. Tetrahedron Lett. 1988, 29, 623.
(10) (a) Collington, E. W.; Myers, A. I. J. Org. Chem. 1971, 36, 3044.
(b) Ziegler, F. E.; Klein, S. I.; Pati, U. K.; Wang, T.-F. J. Am. Chem. Soc.
1985, 107, 7230.
a Reaction conditions: (a) Bu3SnH, Pd(Ph3P)2Cl2; (b) I2 (81%
two-steps); (c) Pd(PPh3)2Cl2, CuI, Et3N, TMSCtCH (93%); (d)
NaOH (99%); (e) MsCl, Et3N.
Org. Lett., Vol. 4, No. 22, 2002
3933

nation of this propargylic acetate followed by iodinolysis
gave vinylic iodide 33, which was coupled with TMS
acetylene and subsequently desilylated and saponified to
afford the alcohol 35 in high yield. Hydrogenolysis of the
hydroxymethyl group of alcohol 35 was effected by the
previous two-step procedure to complete the sequence. Enyne
38 (F in Figure 1) was thus produced in 82% overall yield.
This intermediate was converted to callystatin A along the
lines of our previous report.2d
related biologically important natural products.15 Studies
along these lines will be disclosed in due course.16
Acknowledgment. This research project was supported
by Grant R01 CA90383 from the National Cancer Institute
of the NIH.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The present modified route to enyne 38 from stereotriad
29 proceeds with one less step and considerably higher
efficiency (46 vs 30% overall yield) compared to the previous
synthesis.2d The regioselective hydrostannation methodology
should find additional applications in polyketide synthesis,
as the propargylic acetate precursors can be prepared in high
enantiomeric purity from chiral allenylmetal reagents. Fur-
thermore, enynes such as 34 and 35 could serve as precursors
to more highly oxygenated analogues of callystatin A and
OL026791M
(15) For example, leptomycin and the leptofuranins: Kobayashi, M.;
Wang, W.; Tsutsui, Y.; Sugimoto, M.; Murakami, N. Tetrahedron Lett.
1998, 39, 8291. Hayakawa, Y.; Sohda, K. Y.; Seto, H. J. Antibiotics 1995,
954.
(16) (E)-anti-1-Acetoxy-5-(tert-butyldimethylsilyloxy)-4-methyl-7-
phenyl-2-tributylstannyl-2-heptene (17). General Procedure for the
Hydrostannation of Alkynes. To a solution of propargylic acetate 13 (0.020
g, 0.054 mmol) in 1 mL of THF was added (PPh3)2PdCl2 (0.0019 g, 0.0027
mmol). The reaction mixture was stirred for 5 min, and Bu3SnH (0.021
mL, 0.080 mmol) was added dropwise over 1 min. The solution turned
black, and H2 was evolved toward the end of the addition. The reaction
mixture was stirred for 15 min and concentrated under reduced pressure.
Flash chromatography on silica gel (100% hexanes) afforded vinylstannane
17 (0.030 g, 83% yield) as a yellow oil: Rf ) 0.30 (1% EtOAc-hexane);
(11) Super Hydride ) LiBEt3H. Aldrich Catalog no. 19 972-8.
(12) An initial application of this hydrogenolysis procedure yielded the
allene elimination product i exclusively. This result was subsequently not
reproducible.
1
IR (film) 1737, 1606 cm-1; H NMR (CDCl3) δ 7.28-7.24 (m, 5H), 5.69
(dt, J ) 10.0, 2.0 Hz, 1H), 4.85 (A of ABX, J ) 13.0, 2.0 Hz, 1H), 4.78
(B of ABX, J ) 13.0, 2.0 Hz, 1H), 3.62-3.56 (m, 1H), 2.70-2.51 (m,
3H), 2.05 (s, 3H), 1.74-1.69 (m, 2H), 1.52-1.44 (m, 6H), 1.34-1.28 (m,
6H), 0.98 (d, J ) 7.5 Hz, 3H), 0.91-0.86 (m, 24H), 0.05 (s, 6H), 13CNMR
(CDCl3) δ 170.76, 144.35, 142.46, 138.39, 128.32, 128.26, 125.66, 75.21,
66.62, 38.62, 36.96, 32.00, 29.11, 27.32, 25.41, 21.03, 18.11, 17.26, 13.67,
10.03, -4.19, -4.42. Anal. Calcd For C34H62O3SiSn: C, 61.35; H, 9.39.
Found: C, 61.49; H, 9.50.
(13) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
(14) This procedure was developed by Greg Schaff in our laboratory. A
detailed report will be forthcoming.
3934
Org. Lett., Vol. 4, No. 22, 2002