Transannular macrocyclization via intramolecular B-alkyl Suzuki reaction

Article abstract of DOI:10.1021/ol0062547

(equation presented) Transannular macrocyclizations via intramolecular B-alkyl Suzuki reactions are described. Regioselective terminal olefin hydroboration with 9-BBN followed by Pd(0)-catalyzed Suzuki reaction in the presence of a base such as TIOEt at h

Full text of DOI:10.1021/ol0062547

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2695-2698
Transannular Macrocyclization via
Intramolecular B-Alkyl Suzuki Reaction
Sherry R. Chemler and Samuel J. Danishefsky*
Department of Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research
1275 York AVenue, New York, New York 10021, and Department of Chemistry,
Columbia UniVersity, HaVemeyer Hall, New York, New York 10027
s-danishefsky@ski.mskcc.org
Received June 23, 2000
ABSTRACT
Transannular macrocyclizations via intramolecular B-alkyl Suzuki reactions are described. Regioselective terminal olefin hydroboration with
9-BBN followed by Pd(0)-catalyzed Suzuki reaction in the presence of a base such as TlOEt at high dilution generates macrocycles with a high
degree of control over olefin geometry with isomerically pure E or Z vinyl iodide substrates. These reactions are complementary to ring
closing metathesis (RCM) macrocyclizations and may prove superior in cases where control of olefin geometry is required.
The intermolecular B-alkyl Suzuki reaction1,2 has emerged
as a valuable method for the construction of sp2-sp3 C-C
bonds. Its growing application is evidenced by its use in
methodology demonstrations3 and in natural product syn-
theses.4 This reaction played a key role in our total syntheses
of epothilones A and B4e as well as in 7-epi-Cp-263,1144f,g
and halichlorine.4h
In contrast, the intramolecular variant of the B-alkyl Suzuki
reaction has not found wide usage. Although the formation
of five- and six-membered rings has been reported to occur
in a facile manner,5 the closing of larger ring sizes through
intramolecular B-alkyl Suzuki reaction has been reported in
either very poor yield or not at all.6 Several years ago we
attempted to effect a route to epothilone A via an intramo-
lecular B-alkyl Suzuki reaction. However, none of the desired
product was obtained.7 Nonetheless, possible approaches to
the total synthesis of several contemporary natural products
(including phomactin A,8,9 Figure 1) occasioned revisitation
of such a possibility.
(1) (a) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A. Tetrahedron
Lett. 1986, 27, 6369. (b) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa,
M.; Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314. (c) Oh-e, T.;
Miyayra, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201. (d) Sato, M.;
Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405.
(2) For recent mechanistic studies, see: (a) Ridgway, B. H.; Woerpel,
K. A. J. Org. Chem. 1998, 63, 458. (b) Matos, K.; Soderquist, J. A. J. Org.
Chem. 1998, 63, 461.
(3) For use in recent methodologies, see: (a) Corey, E. J.; Roberts, B.
E. Tetrahedron Lett. 1997, 38, 8919. (b) Sasaki, M.; Fuwa, H.; Inoue, M.;
Tachibana, K. Tetrahedron Lett. 1998, 39, 9027. (c) Kamatani, A.; Overman,
L. E. J. Org. Chem. 1999, 64, 8743. (d) Sabat, M.; Johnson, C. R. Org.
Lett. 2000, 2, 1089.
(4) For use in recent total syntheses, see: (a) Johnson, C. R.; Braun, M.
P. J. Am. Chem. Soc. 1993, 115, 11014. (b) Ohba, M.; Kawase, N.; Fujii,
T. J. Am. Chem. Soc. 1996, 118, 8250. (c) Narukawa, Y.; Nishi, K.; Onoue,
H. Tetrahedron 1997, 53, 539. (d) Trost, B. M.; Lee, C. B. J. Am. Chem.
Soc. 1998, 120, 6818. (e) Balog, A.; Harris, C.; Savin, K.; Zhang, K.-G.;
Chou, T.-C.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 2675. (f)
Meng, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1999, 38, 1485. (g)
Meng, D.; Tan, Q.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1999, 38,
3197. (h) Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 1999, 38, 3542. (i) Marshall, J. A.; Johns, B. A. J. Org. Chem.
1998, 63, 7885. (j) Fu¨rstner, A.; Konetzki, I. J. Org. Chem. 1998, 63, 3072.
(5) (a) Miyaura, N.; Ishikawa, M.; Suzuki, A. Tetrahedron Lett. 1992,
33, 2571. (b) Soderquist, J. A.; Leon, G.; Colberg, J. C.; Martinez, I.
Tetrahedron Lett. 1995, 36, 3119.
(6) (a) Kwochka, W. R.; Damrauer, R.; Schmidt, M. W.; Gordon, M.
W. Organometallics 1994, 13, 3728. (b) Smith, B. B.; Kwochka, W. R.;
Damrauer, R.; Swope, R. J.; Smyth, J. R. J. Org. Chem. 1997, 62, 8589.
(c) Bracher, F.; Schulte, B. J. Chem. Soc., Perkin Trans. 1 1996, 2619.
(7) Meng, D.; Su, D.-S. 1997, unpublished results from our labs.
(8) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano,
H.; Hata, T.; Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463.
10.1021/ol0062547 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/25/2000

context of transannular macrocyclization. Such a capability
could serve well in a synthetic venture directed at phomactin
A. The E and Z vinyl iodides 7 and 8, respectively, were
designed to help address the overall feasibility issue. These
compounds were synthesized as shown in Scheme 1.
Scheme 1
Figure 1.
The most obvious advantage of the intramolecular B-alkyl
Suzuki reaction over the complementary ring closing me-
tathesis (RCM) reaction is the potentially higher degree of
control of olefin geometry of the resulting macrocyclic
adduct. Lack of control of olefin geometry is a common
problem associated with macrocyclizations via RCM.10
Conversely, several methods for the stereoselective genera-
tion of the vinyl iodides which are relevant to the Suzuki
substrates have been reported.11 Thus, one can imagine the
stereospecific formation of exocyclic as well as E and Z
disubstituted, trisubstituted, and even tetrasubstituted olefins
contained in macrocycles via this transformation (potential
intramolecular B-alkyl Suzuki transformations, eqs 1-3).
Ketone 112 was stereoselectively converted to the tertiary
silyl ether 2, which upon hydroboration and removal of the
dithiane ketal12b yielded 3. Protection of the primary alcohol
followed by deconjugation of the olefin yielded ketone 4.
(11) Methods for E vinyl iodide synthesis: (a) Takai, K.; Nitta, K.;
Utimo, K. J. Am. Chem. Soc. 1986, 108, 7408. (b) Evans, D. A.; Black, W.
C. J. Am. Chem. Soc. 1993, 115, 4497. (c) Brown, H. C.; Hamaoka, T.;
Ravindran, N. J. Am. Chem. Soc. 1973, 95, 5786. Methods for Z vinyl iodide
synthesis: (d) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173. (e)
Concellon, J. M.; Bernad, P. L.; Perez-Andrez, J. A. Angew. Chem., Int.
Ed. 1999, 38, 2384. (f) Corey, E. J.; Cashman, J. R.; Eckrich, T. M.; Corey,
D. R. J. Am. Chem. Soc. 1985, 107, 713. Methods for trisubstituted vinyl
iodides: (g) Negishi, E.-i.; Van Horn, D. E.; King, A. O.; Okukado, N.
Synthesis 1979, 501. (h) Chen, J.; Wang, T.; Zhao, K. Tetrahedron Lett.
1994, 35, 2827.
Our initial objective in this program was to establish the
feasibility of the ring-closing B-alkyl Suzuki reaction in the
(9) For partial syntheses and syntheses of related structures, see: Foote,
K. M.; Hayes, C. J.; Pattenden, G. Tetrahedron Lett. 1996, 37, 275. (b)
Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Tetrahedron Lett. 1996, 37,
7107.
(10) (a) Control of olefin geometry in the RCM reaction has been reported
to be problematic in several instances. Several key references are cited by
Fu¨rstner, A.; Grela, K. Angew. Chem., Int. Ed. 2000, 39, 1234. (b) For an
impressive example of attainment of stereoselectivity by RCM, see: Houri,
A. F.; Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1995, 117,
2943.
(12) (a) Bosch, M. P.; Camps, F.; Coll, J.; Guerrero, A.; Tatsuoka, T.;
Meinwald, J. J. Org. Chem. 1986, 51, 773. (b) Golinski, M.; Brock, C. P.;
Watt, D. S. J. Org. Chem. 1993, 58, 159.
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Org. Lett., Vol. 2, No. 17, 2000

Stereoselective allylation of 4 and protection of the resulting
tertiary alcohol as a methyl ether13 gave 5.14 Silyl ether 5
was converted to aldehyde 615 which in turn was used to
provide the E and Z vinyl iodides 7 and 8 using the methods
of Takai11a,b and Stork,11d respectively.
Scheme 2
Gratifyingly, the intramolecular B-alkyl Suzuki reaction
of vinyl iodide 7 using aqueous CsCO3 as the base afforded
macrocycle 9 in 40% yield (eq 4). A dramatic improvement
to 60% yield was realized when TlOEt was used as the
base.16 Using the latter conditions, macrocyclization of Z
vinyl iodide 8 was also effected, forming 10 in 46% yield
(eq 5). Not surprisingly, selective hydroboration of the
higher order oligomeric products. Thus, it appears that in
this case the intramolecular B-alkyl Suzuki macrocyclization
is superior to the RCM even at the level of gross feasibility.
In a cursory effort to establish the scope and limitations
of the intramolecular B-alkyl Suzuki reaction, three other
substrates were investigated (eqs 6-8). Compounds 13 and
terminal olefin in the presence of the vinyl iodide and
trisubstituted olefin moieties of these substrates was
realized.4b,17
We were interested in comparing the efficiency and
selectivity (E vs Z) of the B-alkyl Suzuki macrocyclizations
of 7 and 8 with the ring-closing metathesis of the corre-
sponding substrate 12 (Scheme 2). The latter was prepared
in four steps from intermediate 5, a common precursor to
vinyl iodides 7 and 8. A conversion of a terminal olefin (cf.
5) to a two-carbon homologated terminal olefin (cf. 11) was
devised for this purpose. This method involved an apparently
unprecedented B-alkyl Suzuki hydrovinylation reaction18 with
vinyl bromide with maintenance of double bond integrity.19
Attempted RCM of substrate 12 with Grubbs’ catalyst20
[(Cy3P)2Cl2RudCHPh] afforded a mixture of dimeric and
(13) Posner, G. H.; Babiak, K. A.; Loomis, G. L.; Frazee, W. J.; Mittal,
R. D.; Karle, I. L. J. Am. Chem. Soc. 1980, 102, 7498.
(14) The corresponding tertiary allylic ether, derived from the conjugated
ketone, was highly unstable under a variety of conditions.
(15) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(16) (a) Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.; Roush,
W. R. Org. Lett. 2000, 2, 2691. (b) Humphrey, J. M.; Aggen, J. B.;
Chamberlin, A. R. J. Am. Chem. Soc. 1996, 118, 11759.
(17) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(18) An analogous hydrovinylation using a Negishi-type coupling has
been reported by Hoveyda, see ref 10b.
15 bearing o-iodo substituents proved to be relatively poor
substrates for the cyclization reaction, yielding seven-
membered ring 14 (eq 6) and ten-membered ring 16 (eq 7)
in 22% and 23% yields, respectively. Increasing the ring size
(19) Pd-catalyzed olefin isomerization is a potential problem. See:
Whang, K.; Cooke, R. J.; Okay, G.; Cha, J. K. J. Am. Chem. Soc. 1990,
112, 8985.
(20) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039.
Org. Lett., Vol. 2, No. 17, 2000
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and extending the centers of reactivity away from the
aromatic ring, as in substrate 17, led to an improvement of
the cyclization efficiency (eq 8). The issues of scope and
limitations of our findings will require more study.
In summary, we have demonstrated that the B-alkyl Suzuki
reaction can be an effective method for transannular mac-
rocyclization. This reaction is complementary to ring-closing
metathesis and potentially offers greater control over olefin
geometry. We are encouraged by the promising results
obtained with 7 and 8. Application of this methodology to
the total synthesis of appropriately challenging target struc-
tures is in progress.
Acknowledgment. NIH Postdoctoral Fellowship support
is gratefully acknowledged by S.R.C. (F32 AI10439-01). We
would also like to thank Professor W. R. Roush and co-
workers at the University of Michigan for disclosing to us
their preliminary results, in which they developed the use
of TlOEt and H2O in Suzuki couplings.
Supporting Information Available: Experimental pro-
cedures and full characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0062547
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Org. Lett., Vol. 2, No. 17, 2000