A synthesis of the C1-C15 domain of the halichondrins

Article abstract of DOI:10.1016/j.tetlet.2008.03.018

A concise route to the C1-C15 domain of the halichondrins is described. The key reaction is the conversion of a furfuryl alcohol to a pyranone. The stereocenter of this pyranone serves as the starting point for the other eight stereocenters.

Full text of DOI:10.1016/j.tetlet.2008.03.018

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2939–2941
A synthesis of the C1–C15 domain of the halichondrins
Katrina L. Jackson, James A. Henderson, Jonathan C. Morris ,
Hajime Motoyoshi, Andrew J. Phillips *
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309-0215, USA
Received 29 December 2007; accepted 5 March 2008
Available online 8 March 2008
Abstract
A concise route to the C1–C15 domain of the halichondrins is described. The key reaction is the conversion of a furfuryl alcohol to a
pyranone. The stereocenter of this pyranone serves as the starting point for the other eight stereocenters.
Ó 2008 Elsevier Ltd. All rights reserved.
In the context of the development of new reactions and
MeO2C
strategies, the halichondrin class of marine macrolides1 has
provided a substantial amount of inspiration to the synthe-
sis community.2,3 The gross structures of these molecules,
as exemplified by halichondrin B (1, Fig. 1), are character-
ized by a 2,6,9-trioxatricyclo[3.3.2.03,7]decane ring system
embedded within a 31-membered lactone, and the presence
MeO2C
BnO
H
O
H
O
O
H
O
H
H
O
OH
TBSO
O
O
TBSO
O
3
2
Nozaki-Hiyama-Kishi
and cross metathesis
OBn
of
a number of polyoxygenated pyranopyrans and
MeO2C
MeO2C
olefination
and [O]
furopyrans.
H
O
H
O
H
O
H
O
We recently initiated studies directed toward the devel-
opment of a total synthesis of the halichondrins,4 and in
this Letter we describe a concise synthesis of the C1–C15
H
TBSO
O
TBSO
CHO
TBSO
TBSO
5
4
hetero-Michael
H
H
H
H
H
H
MeO2C
1
O
O
Achmatowicz
O
H
H
HO
O
H
O
O
O
O
HO
O
O
H
OH
O
O
O
HO
HO
O
OBz
OBz
O
H
O
O
O
6
7
8
O
halichondrin B, 1
15
Fig. 2. Overall synthesis plan for C1–C15.
O
domain of the halichondrins. An overview of the retrosyn-
thesis of the C1–C15 subunit, 2, is presented in Figure 2. As
can be seen, these plans are predicated on the use of the
Achmatowicz oxidation for the conversion of a furfuryl
alcohol to a pyranone (e.g., 8?7), which would serve as
a template for the synthesis of the fully functionalized
C1–C11 pyranopyran, 4.
Fig. 1. Halichondrin B.
*
Corresponding author. Tel.: +1 303 735 2049; fax: +1 303 492 0439.
E-mail address: Andrew.Phillips@colorado.edu (A. J. Phillips).
School of Chemistry and Physics, The University of Adelaide,
Australia 5005.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.018

2940
K. L. Jackson et al. / Tetrahedron Letters 49 (2008) 2939–2941
The departure point for our venture was known alcohol
odinane, 99%). The introduction of a vinyl group was best
achieved using vinyl iodide under Nozaki–Hiyama–Kishi
reaction conditions to give a 7:1 ratio of the desired prod-
uct 18 to the undesired diastereoisomer in 85% combined
yield. All other methods for the introduction of this group
favored the chelation-controlled addition to produce the
undesired diastereoisomer. The cross metathesis of 18
and 21 (10 equiv) to produce enone 19 was possible in
81% yield using 5 mol % of the Hoveyda–Blechert catalyst
1613 in toluene at 80 °C. Gratifyingly, when this enone was
subjected to the aqueous HF conditions reported by Burke
et al.,14 global desilylation, followed by hetero-Michael
85,6 (Scheme 1), which was subjected to Achmatowicz
oxidation7,8 with tert-butylhydroperoxide as an oxidant
and VO(acac)2 as a catalyst to produce an intermediate pyr-
anone hemiacetal in 83% yield. This pyranone hemiacetal
was immediately subjected to O’Doherty’s benzoylation
conditions9 to yield 9 (50%). The reduction of ketone 9 with
NaBH4 gave alcohol 10 in 92% yield. Cross metathesis with
methyl acrylate using 5 mol % of the Hoveyda-Blechert cat-
alyst in CH2Cl2 produced enoate 11 (82%), which was readily
cyclized to pyranopyran 12 in 70% yield upon exposure to
TBAF in THF. The subsequent Grieco oxidation10 of 12
with m-CPBA in the presence of BF3ÁOEt2 produced lactone
13 (85%). Dihydroxylation with catalytic OsO4 and NMO
produced a very water-soluble diol that was immediately
subjected to TBSOTf in the presence of 2,6-lutidine to give
bis-TBS ether 14 in 58% yield over the two steps. At this junc-
ture, we were able to exercise a selective olefination of the lac-
tone carbonyl group using the Petasis reagent11 in 71% yield,
and the enol ether was subjected to hydroboration with
BH3ÁTHF and subsequent oxidation with basic H2O2 to give
the desired alcohol 15 in 48% yield. The assignment of the
stereochemistry of this compound proved problematic, pri-
marily due to the compression of 3JH,H coupling constants.
Ultimately, in order to unequivocally determine the stereo-
chemistry we resorted to the preparation of an authentic
sample of this compound using Kishi’s reported route.12
The comparison of the material obtained by that route,
and the material prepared by the route described in Scheme
1 showed that they were identical.
MeO2C
MeO2C
H
O
1
H
O
2
O
H
O
H
OH
TBSO
CHO
TBSO
TBSO
15
TBSO
17
MeO2C
H
O
O
H
MeO 2
C
H
O
H
O
O
H
3
OH
TBSO
H
OH
TBSO
TBSO
TBSO
19
18
OBn
MeO2C
H
O
4
O
H
O
H
21
BnO
O
O
O
BnO
2
With a route to alcohol 15 secured, we were able to eval-
uate the utility of cross metathesis for the introduction of
the enone required for the formation of the 2,6,9-trioxatri-
cyclo[3.3.2.03,7]decane ring system (Scheme 2). To this end,
alcohol 15 was oxidized to aldehyde 17 (Dess–Martin peri-
Scheme 2. Reagents and conditions: (1) Dess–Martin periodinane,
CH2Cl2, 99%; (2) vinyl iodide, 1% NiCl2/CrCl2, THF, 40 °C, 85%
(dr = 7:1); (3) 1-(benzyloxy)but-3-en-2-one (21), 5 mol % Hoveyda–Blec-
hert catalyst 16, PhMe, 80 °C, 81%; (4) (a) 48% aq HF, MeCN, 36% or (b)
TBAF, AcOH, then ion-exchange column (see text), 90%.
O
OH
OH
1
2
O
O
O
8
9
10
OBz
OBz
CO2Me
H
CO 2Me
OH
O
O
CO2Me
O
3
4
5
H
H
O
H
11
O
O
12
OBz
13
OBz
CO2Me
CO2Me
H
Mes
N
N M es
O
Cl
Cl
O
Ru
O
6
7
H
H
TBSO
TBSO
TBSO
TBSO
H
O
O
16
15
O
14
OH
Scheme 1. Reagents and conditions: (1) (a) VO(acac)2, TBHP, CH2Cl2, 83%; (b) BzCl, Et3N, DMAP, À78 °C, 50%; (2) NaBH4, CeCl3Á7H2O, CH2Cl2,
MeOH, 92%; (3) methyl acrylate, 5 mol % Hoveyda–Blechert catalyst 16, CH2Cl2, 82%; (4) TBAF, THF, 70%; (5) m-CPBA, BF3ÁOEt2, CH2Cl2, À10 °C to
rt, 85%; (6) (a) OsO4, NMO, t-BuOH–Me2CO–H2O; (b) TBSOTf, 2,6-lutidine, CH2Cl2, À78 to 0 °C, 58% (2 steps); (7) (a) Cp2TiMe2, THF–PhMe, 65 °C,
2 days, 71%; (b) BH3ÁTHF, THF, then H2O2–NaOH, 48%.

K. L. Jackson et al. / Tetrahedron Letters 49 (2008) 2939–2941
2941
8. For early examples of the Achmatowicz oxidation see: (a) Ach-
matowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwierzchowska, Z.;
Zamojski, A. Tetrahedron 1971, 1973; (b) Cavill, G. W.; Laing, D. G.;
Williams, P. J. Aust. J. Chem. 1969, 2145; (c) Lefebvre, Y.
Tetrahedron Lett. 1972, 133.
9. Harris, J. M.; Keranen, M. D.; Nguyen, H.; Young, V. G.;
O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17.
10. Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett. 1978,
419.
addition and acetalization gave the desired structure X in
36% yield.15 This yield could be dramatically improved
by the application of Kishi’s recently reported non-aque-
ous desilylation workup protocol16 followed by ketal
formation using Kishi’s ion-exchange column system.17
Under these conditions, the desired compound was
obtained in 90% yield.
In summary, we have described a concise route to the
C1–C15 domain of the halichondrins that is based on an
Achmatowicz reaction of a furfuryl alcohol. This oxidation
produces a pyranone that serves as the template for the
remaining stereocenters. Further applications of this strat-
egy and progress toward the synthesis of the halichondrins
will be reported in due course.
11. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
12. Aicher, T. D.; Kishi, Y. Tetrahedron Lett. 1987, 28, 3463.
13. (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168; (b) Gessler, S.; Randl, S.; Blechert,
S. Tetrahedron Lett. 2000, 41, 9973.
14. Burke, S. D.; Jung, K. W.; Phillips, J. R.; Perri, R. E. Tetrahedron
Lett. 1994, 35, 703.
15. The NMR data for the final compounds matched those reported by
Burke et al. (coupling constants in Hz):
Acknowledgments
2
4
1
3
5
MeO2C
We thank Eli Lilly and Company (via Lilly Grantee Pro-
gram), the AP Sloan Foundation, and the National Cancer
Institute (CA 110246) for support of this research. We
thank Melissa Highfill for preliminary studies.
H
O
6
O
H
7
H
8
9
10
O
O
11
O
13
BnO
12
14
15
References and notes
Position
Burke 1H d (CDCl3)
Phillips 1H d (CDCl3)
1. (a) Uemura, D.; Takahashi, K.; Yamamoto, K.; Yamamoto, T.;
Katayama, C.; Tanaka, J.; Okumura, Y.; Hirata, Y. J. Am. Chem.
Soc. 1985, 107, 4796; (b) Hirata, Y.; Uemura, D. Pure Appl. Chem.
1986, 58, 701; (c) Pettit, G. R.; Tan, R.; Gao, F.; Williams, M. D.;
Doubek, D. L.; Boyd, M. R.; Schmidt, J. M.; Chapuis, J. C.; Hamel,
E.; Bai, R.; Hooper, J. N. A.; Tackett, L. P. J. Org. Chem. 1993, 58,
2538; (d) Litaudon, M.; Hickford, S. J. H.; Lill, R. E.; Lake, R. J.;
Blunt, J. W.; Munro, M. H. G. J. Org. Chem. 1997, 62, 1868.
2. Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.;
Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J.
Am. Chem. Soc. 1992, 114, 3162.
3. For representative examples see the following papers and references
cited therein: (a) Namba, K.; Jun, H.-S.; Kishi, Y. J. Am. Chem. Soc.
2004, 126, 7770; (b) Keller, V. A.; Kim, I.; Burke, S. D. Org. Lett.
2005, 7, 737; (c) Horita, K.; Nishibe, S.; Yonemitsu, O. Phytochem.
Phytopharm. 2000, 386; (d) Cooper, A. J.; Pan, W.; Salomon, R. G.
Tetrahedron Lett. 1993, 34, 8193.
CO2Me
2a
2b
3
4a
4b
5a
5b
6
7
8
9
10
11
12
13
3.61–3.66 (m)
3.64 (s, 3H)
2.41 (dd, J = 15.8, 5.0)
2.49 (dd, J = 15.8, 8.1)
3.81 (m)
1.33 (m)
1.73 (m)
2.41 (dd, J = 15.8 5.1)
2.48 (dd, J = 15.8, 7.9)
3.80 (m)
1.26–1.45 (m)
1.73 (m)
1.26–1.45 (m)
2.02 (m)
4.25 (m)
2.97 (dd, J = 9.6, 1.8)
4.39 (dd, J = 3.6, 1.7)
4.13 (dd, J = 6.6, 3.8)
4.20 (dd, J = 6.6, 4.5)
4.64 (dd, J = 4.5, 4.4)
4.71 (dd, J = 4.8, 4.6)
1.97 (d, J = 13.4)
3.60–3.67 (m)
1.41 (m)
2.04 (m)
4.25 (ddd, J = 10.0, 9.6, 4.4)
2.97 (dd, J = 9.6, 1.8)
4.39 (dd, J = 3.9, 1.8)
4.14 (dd, J = 6.5, 3.9)
4.20 (dd, J = 6.5, 4.5)
4.65 (dd, J = 4.5, 4.4)
4.71 (dd, J = 5.0, 4.4)
1.98 (d, J = 13.4)
3.61–3.66 (m)
3.61–3.66 (m)
4.69 (d, J = 12.2)
4.71 (dd, J = 5.0, 4.4)
7.26–7.36 (m)
15a
15b
PhCHH
PhCHH
Ph
4. Henderson, J. A.; Jackson, K. L.; Phillips, A. J. Org. Lett. 2007, 9,
5299.
3.60–3.67 (m)
4.69 (d, J = 12.1)
4.71 (dd, J = 4.8, 4.6)
7.23–7.36 (m)
5. Furstner, A.; Nagano, T. J. Am. Chem. Soc. 2007, 129, 1906.
¨
6. All new compounds were fully characterized by 1H and 13C NMR,
HRMS and IR.
7. The oxidation of furans to butenolides has been known since the mid-
1960s. See, for example: Ferland, J. M.; Lefebvre, Y.; Deghenghi, R.;
Wiesner, K. Tetrahedron Lett. 1966, 3617 and references cited therein.
16. Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723.
17. See Ref. 3a.