Halichondrin B: Synthesis of the C(1)-C(15) subunit

4070

J . Org. Chem. 2000, 65, 4070-4087

Ha lich on d r in B: Syn th esis of th e C(1)-C(15) Su bu n it

Steven D. Burke,* Kyung Woon J ung, William T. Lambert, J eannie R. Phillips, and

J ason J . Klovning

Department of Chemistry, University of WisconsinsMadison, Madison, Wisconsin 53706-1396

Received February 2, 2000

A short and efficient synthesis of the C(1)-C(15) subunit of halichondrin B in its natural

configuration is described. The polycyclic caged ketal 3, containing nine asymmetric centers, is

prepared in 14 steps from R-^D-glucoheptonic acid γ-lactone (7). Key steps in the two similar routes

described include EtMgBr-promoted pinacol ring expansions of hydroxy mesylates 23 and 34,

intramolecular Michael additions of 29 and 37, and a one-pot, HF-induced conversion of 4 to 3

involving in situ silyl ether cleavage, acetal hydrolysis, Michael addition, and caged ketal formation.

Alternative protocols for carbinol inversion at C(11), one early and one late in the synthetic sequence,

are also described.

In tr od u ction

Halichondrin B (Figure 1) is the most potent in a

family of cytotoxic polyether macrolides that have been

isolated in low yields (1.8 × 10^-8to 4.0 × 10^-5%) from

four marine sponge genera, including Halichondria,^1a

Axinella,^1b,cPhakellia,^1dand Lissodendoryx.^1e

The halichondrins are mitotic inhibitors, and halichon-

drin B displays potent in vivo activity against a number

of chemoresistant human solid tumor xenografts, includ-

ing LOX melanoma, KM20L colon, FEMX melanoma, and

OVCAR-3 ovarian tumor, in immune-deficient mice.²

Researchers at the National Cancer Institute (NCI) have

established that halichondrin B binds to the vinca

domain of tubulin, thereby inhibiting tubulin polymeri-

zation and tubulin-dependent GTP hydrolysis.³Halichon-

drin B displays an IC₅₀value for L1210 murine leukemia

cells of 0.3 nM, making it one of the most potent

inhibitors in a class that includes dolastatin 10 (0.5 nM),

rhizoxin (1nM), and vinblastine (20 nM).³Hirata and

Uemura observed that increased activity among hali-

chondrin congeners is directly related to the lipophilicity

of the 2,6,9-trioxatricyclo[3.3.2.0^3,7]decane ring system

F igu r e 1.

(rings C, D, and E; the “cage”) and the hydrophilicity of

the C(50) “tail” of the halichondrins.^1aMore recently,

Kishi and co-workers discovered that the C(1)-C(38) diol

used in their total synthesis has an activity profile which

(4) (a) Stamos, D. P.; Chen, S. S.; Kishi, Y. J . Org. Chem. 1997, 62,

7552-7553. (b) Aicher, T. D.; Kishi, Y. Tetrahedron Lett. 1987, 28,

3463-3466. (c) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C.

J .; J ung, S. H.; Kishi, Y.; Scola, P. M. Tetrahedron Lett. 1992, 33, 1549-

1552. (d) Buszek, K. R.; Fang, F. G.; Forsyth, C. J .; J ung, S. H.; Kishi,

Y.; Scola, P. M.; Yoon, S. K. Tetrahedron Lett. 1992, 33, 1553-1556.

(e) Fang, F. G.; Kishi, Y.; Matelich, M. C.; Scola, P. M. Tetrahedron

Lett. 1992, 33, 1557-1560. (f) Duan, J . J .-W.; Kishi, Y. Tetrahedron

Lett. 1993, 34, 7541-7544. (g) Stamos, D. P.; Kishi, Y. Tetrahedron

Lett. 1996, 37, 8643-8646. (h) Aicher, T. D.; Buszek, K. R.; Fang, F.

G.; Forsyth, C. J .; J ung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.;

Spero, D. M.; Yoon, S. K. J . Am. Chem. Soc. 1992, 114, 3162-3164.

(5) Munro, M. H. G.; Blunt, J . W.; Dumdei, E. J .; Hickford, S. J . H.;

Lill, R. E.; Li, S.; Battershill, C. N.; Duckworth, A. R. J . Biotech. 1999,

70, 15-25.

* To whom all correspondence should be sent. Phone: (608) 262-

4941. Fax: (608) 265-4534. E-mail: burke@chem.wisc.edu.

(1) (a) Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701-

710. (b) Pettit, G. R.; Herald, C. L.; Boyd, M. R.; Leet, J . E.; Dufresne,

C.; Doubek, D. L.; Schmidt, J . M.; Cerny, R. L.; Hooper, J . N. A.;

Rutzler, K. C. J . Med. Chem. 1991, 34, 3339-3340. (c) Pettit, G. R.;

Gao, F.; Doubek, D. L.; Boyd, M. R.; Hamel, E.; Bai, R.; Schmidt, J .

M.; Tackett, L. P.; Rutzler, K. Gazz. Chim. Ital. 1993, 123, 371-377.

(d) 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, 2538-2543. (e) Litaudon,

M.; Hart, J . B.; Blunt, J . W.; Lake, R. J .; Munro, M. H. G. Tetrahedron

Lett. 1994, 35, 9435-9438.

(2) (a) Personal correspondence with M. R. Boyd, M.D., Ph. D.,

Cancer Research Center, Frederick, MD, National Cancer Institute.

Dr. Boyd shared with us data and slides that resulted in the NCI

Decision Network Committee’s selection of halichondrin B for drug

development. (b) Personal correspondence with E. Hamel, M.D., Ph.D.,

National Institute of Health, National Cancer Institute. Dr. Hamel

informed us that halichondrin B cures in vivo human tumor xenografts

transplanted in immune deficient mice.

(6) (a) Kim, S.; Salomon, R. G. Tetrahedron Lett. 1989, 30, 6279-

6282. (b) Cooper, A. J .; Salomon, R. G. Tetrahedron Lett. 1990, 31,

3813-3816. (c) DiFranco, E.; Ravikumar, V. T.; Salomon, R. G.

Tetrahedron Lett. 1993, 34, 3247-3250. (d) Cooper, A. J .; Pan, W.;

Salomon, R. G. Tetrahedron Lett. 1993, 34, 8193-8196.

(7) (a) Horita, K.; Hachiya, S.; Nagasawa, M.; Hikota, M.; Yone-

mitsu, O. Synlett 1994, 38-40. (b) Horita, K.; Nagasawa, M.; Hachiya,

S.; Yonemitsu, O. Synlett 1994, 40-43. (c) Horita, K.; Sakurai, Y.;

Nagasawa, M.; Hachiya, S.; Yonemitsu, O. Synlett 1994, 43-45. (d)

Horita, K.; Sakurai, Y.; Nagasawa, M.; Maeno, K.; Hachiya, S.;

Yonemitsu, O. Synlett 1994, 46-48. (e) Horita, K.; Hachiya, S.;

Ogihara, K.; Yoshida, Y.; Nagasawa, M.; Yonemitsu, O. Heterocycles

1996, 42, 99-104. (f) Horita, K.; Nagasawa, M.; Hachiya, S.-i.; Sakurai,

Y.; Yamazaki, T.; Uenishi, J .; Yonemitsu, O. Tetrahedron Lett. 1997,

38, 8965-8968. (g) Horita, K.; Hachiya, S.-i.; Yamazaki, T.; Naitou,

T.; Uenishi, J .; Yonemitsu, O. Chem. Pharm. Bull. 1997, 45, 1265-

1281. (h) Horita, K.; Sakurai, Y.; Nagasawa, M.; Yonemitsu, O. Chem.

Pharm. Bull. 1997, 45, 1558-1572. (i) Yonemitsu, O.; Yamazaki, T.;

Uenishi, J .-i. Heterocycles 1998, 49, 89-92. (j) Horita, K.; Nagasawa,

M.; Sakurai, Y.; Yonemitsu, O. Chem. Pharm. Bull. 1998, 46, 1199-

1216.

(3) (a) Hamel, E. Pharmac. Ther. 1992, 55, 31-51. (b) Bai, R.; Paull,

K. D.; Herald, C. L.; Malspeis, L.; Pettit, G. R.; Hamel, E. J . Biol. Chem.

1991, 266, 15882-15889. (c) Paull, K. D.; Lin, C. M.; Malspeis, L.;

Hamel, E. Cancer Res. 1992, 52, 3892-3900. (d) Luduena, R. F.; Roach,

M. C.; Prasad, V.; Pettit, G. R. Biochem. Pharmacol. 1993, 45, 421-

427. (e) Roberson, R. W.; Tucker, B.; Pettit, G. R. Mycol. Res. 1998,

102, 378-382.

Published on Web 06/01/2000

Halichondrin B: Synthesis of the C(1)-C(15) Subunit

J . Org. Chem., Vol. 65, No. 13, 2000 4071

Sch em e 1

is very similar to that of halichondrin B against more

than 60 cancer cell lines with IC₅₀values within 1 order

of magnitude of those displayed by the natural product.^4a

Stage A preclinical development has been recom-

mended for halichondrin B by the National Cancer

Institute,²but the scarcity of this substance has made it

difficult to proceed. Recent work by Munro and co-

workers has resulted in the production of halichondrin

B by aquaculture, although the generation of 5 kg/year

for clinical use would require the aquacultural production

of Lissodendoryx n. sp. in estimated quantities of more

than 5000 tons/year.⁵Synthetic chemists have attempted

to resolve the supply issue through the development of

efficient syntheses of halichondrin B and its segments.

Kishi and co-workers have published the syntheses of

several segments of halichondrin B,⁴including an im-

pressive total synthesis in 1992.^4hSynthetic approaches

to the halichondrins have also been described by Salomon⁶

and Yonemitsu.⁷Additionally, we have reported the

synthesis of several segments of halichondrin B,⁸includ-

ing a brief report on the synthesis of the C(1)-C(15)

segment in 1994.^8bThis paper provides a detailed account

of the synthesis of the C(1)-C(15) segment of halichon-

drin B, including developments subsequent to the earlier

communication.

Resu lts a n d Discu ssion

In our synthetic plan for the total synthesis of hali-

chondrin B, the entire carbon skeleton is to be in place,

with macrolactonization occurring late (Scheme 1). The

macrolactonization precursor 1 is to be obtained by

synthetic manipulation of an adduct of aldehyde 2, which

would, in turn, be prepared by debenzylation and oxida-

tion of the polycyclic caged ketal 3. Compound 3, which

has also been prepared by Salomon and co-workers,^6bis

accessible from the benzyloxymethyl enone 4 via TBS

ether cleavage and selective hydrolysis of the terminal

pentylidene acetal followed by intramolecular Michael

addition of the C(9) hydroxyl to the enone moiety and

caged ketal formation involving the C(8) and C(11)

hydroxyls and the C(14) ketone. Enone 4 arises via Wittig

homologation of aldehyde 5, which is derived from

pyranone 6. The C(6) homoallyl group in compound 6 was

expected to provide a facile means for A-ring installation

to complete the trans-fused dioxadecalin AB-ring system

present in aldehyde 5. Pyranone 6 was envisioned to be

available from the inexpensive carbohydrate derivative

R-^D-glucoheptonic acid γ-lactone (7), following a ring

expansion from furanone to pyranone and installation of

the C(6) homoallyl group. Four of the six stereocenters

in pyranone 6 are correctly set in compound 7, with only

C(11) (halichondrin B numbering) requiring an inversion.

Our first-generation synthesis of the C(1) - C(15)

subunit involved an early-stage inversion at C(11). Ac-

cordingly, the first goal was to selectively protect the

hydroxyls at C(8), C(9), C(12), and C(13) to permit

inversion of stereochemistry at the C(11) carbinol center.

Regioselective bis(acetalization) of 7 with 3-pentanone

and sulfuric acid provided 8, in which the C(11) carbinol

center was exposed for inversion (Scheme 2). Trace

amounts of the bis(acetalization) regioisomer 10 in which

the C(8) hydroxyl was left exposed were also isolated

under these conditions. The mono(acetalization) product

9 was also isolated as a major product. Although the

addition of anhydrous MgSO₄or 4 Å molecular sieves to

the reaction mixture failed to drive the acetalization

equilibrium to completion, resubjection of 9 to the reac-

tion conditions provided additional 8 for an overall yield

of 55%. The use of acetonide protecting groups⁹or other

acid catalysts resulted in the regioisomer analogous to

10 as the major product, in which C(8) was left unpro-

tected.

(8) (a) Burke, S. D.; Buchanan, J . L.; Rovin, J . D. Tetrahedron Lett.

1991, 32, 3961-3964. (b) Burke, S. D.; J ung, K. W.; Phillips, J . R.;

Perri, R. E. Tetrahedron Lett. 1994, 35, 703-706. (c) Burke, S. D.;

Zhang, G.; Buchanan, J . L. Tetrahedron Lett. 1995, 36, 7023-7026.

(d) Burke, S. D.; Phillips, J . R.; Quinn, K. J .; Zhang, G.; J ung, K. W.;

Buchanan, J . L.; Perri, R. E. Synthetic Studies Toward Complex

Polyether Macrolides of Marine Origin. In Anti-Infectives: Recent

Advances in Chemistry and Structure-Activity Relationships; Bentley,

P. H., O’Hanlon, P. J ., Eds.; The Royal Society of Chemistry: Cam-

bridge, 1997; pp 73-85. (e) Burke, S. D.; Austad, B. C.; Hart, A. C. J .

Org. Chem. 1998, 63, 6770-6771. (f) Burke, S. D.; Quinn, K. J .; Chen,

V. J . J . Org. Chem. 1998, 63, 8626-8627. (g) Burke, S. D.; Austad, B.

C.; Hart, A. C. submitted for publication.

With the C(11) hydroxyl now isolated, attention turned

to the inversion of this stereocenter. The failure of one-

(9) (a) Shing, T. K. M.; Tsui, H.-c.; Zhou, Z.-h.; Mak, T. C. W. J .

Chem. Soc., Perkin Trans. 1 1992, 887-893. (b) Shing, T. K. M.; Tsui,

H.-c.; Zhou, Z.-h. J . Chem. Soc., Chem. Commun. 1992, 810-811.

4072 J . Org. Chem., Vol. 65, No. 13, 2000

Burke et al.

Sch em e 2

Sch em e 4

Sch em e 3

oxidant resulted in extensive decomposition. Oxidation

of 8 with various chromium-based oxidants¹³proceeded

in poor yield and incomplete conversion. Furthermore,

subsequent chromatography of the ketone product re-

sulted in decomposition. Fortunately, use of the Dess-

Martin reagent¹⁴gave an excellent yield of ketone 11 that

was of sufficient purity to be carried forward without

further purification (Scheme 4).

Reduction of the ketone 11 to alcohol 13 with the

desired (S)-configuration at C(11) could be carried out

most directly with Zn(BH₄)₂,¹⁵but this reaction proved

inconvenient for large-scale applications (Scheme 4).

Other reducing agents such as NaBH₄, LiBH₄, and

L-Selectride resulted in concomitant reduction at C(7)

and/or poor diastereoselectivity at C(11).^10bThe best

alternative to Zn(BH₄)₂was found to be NaBH₄/CeCl₃‚

7H₂O,¹⁶which gave the overreduced product 12 exclu-

sively. Selective oxidation of the C(7) hemiacetal in 12

with pyridinium dichromate^13aprovided the alcohol 13.

Overoxidation of 12 to ketone 11 under these conditions

required that the reaction be arrested prior to completion,

thereby giving low and variable yields of 13. Compound

13 was then converted to its TBDMS ether 14. Our choice

of masking the C(11) hydroxyl as a TBDMS ether was

based on the need for a robust protecting group that

would suffer cleavage in the presence of fluoride ion

under the conditions required to effect caged ketal

formation. This C(11) carbinol inversion sequence pro-

vides the inverted C(11) TBS ether 14 in four steps and

36% overall yield from compound 8.

step inversion protocols,¹⁰including several variations of

the Mitsunobu reaction,^10e,fnecessitated the use of an

oxidation-reduction sequence to invert the C(11) alcohol.

Many oxidants were surveyed in attempts to convert 8

to the corresponding C(11) ketone. Swern conditions¹¹

provided the desired ketone as a 1:1 mixture of C(10)

epimers, presumably resulting from â-elimination and re-

addition reactions in the Swern intermediate as shown

in Scheme 3. The use of tetrapropylammonium perruth-

enate/N-methylmorpholine N-oxide (TPAP/NMO)¹²as an

(10) (a) Carter, M. B. Ph.D. Thesis, University of Wisconsins

Madison, 1992. (b) J ung, K. W. Ph.D. Thesis, University of Wisconsins

Madison, 1995. (c) Moriarty, R. M.; Zhuang, H.; Penmasta, R.; Liu,

K.; Awasthi, A. K.; Tuladhar, S. M.; Rao, M. S. C.; Singh, V. K.

Tetrahedron Lett. 1993, 34, 8029-8032. (d) Quinn, K. J . University of

WisconsinsMadison, unpublished results. (e) Hughes, D. L. Org. React.

1992, 42, 335-656. (f) Saiah, M.; Bessodes, M.; Antonakis, K.

Tetrahedron Lett. 1992, 33, 4317-4320.

(13) (a) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 20, 399-

402. (b) Corey, E. J .; Suggs, W. J . Tetrahedron Lett. 1975, 16, 2647-

2650.

(14) (a) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113,

7277-7287. (b) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.

(15) Iida, H.; Yamazaki, N.; Kibayashi, C. J . Org. Chem. 1986, 51,

3769-3771 and references cited within.

(11) Swern, D.; Omura, K. Tetrahedron 1978, 34, 1651-1660.

(12) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .

Chem. Soc. Chem. Commun. 1987, 1625-1627.

(16) Luche, J .-L. J . Am. Chem. Soc. 1978, 100, 2226-2227.

Halichondrin B: Synthesis of the C(1)-C(15) Subunit

J . Org. Chem., Vol. 65, No. 13, 2000 4073

Sch em e 5

Sch em e 6

To circumvent the problem of overoxidation in the

conversion of 12 to 13, another strategy was devised that

involved protection of the C(11) alcohol in 12 prior to

hemiacetal oxidation. As depicted in Scheme 5, compound

12 is converted to the bis(tert-butyldimethylsilyl) ether

15 with the expectation that the hemiacetal silyl ether

would be considerably more labile than the C(11) silyl

ether and therefore allow for selective monodeprotection.

Indeed, treatment of 15 with tetrabutylammonium fluo-

ride for 10 min at 0 °C provided the monodeprotected

compound 16 containing a free hemiacetal that was

subsequently oxidized to the desired lactone 14 with

pyridinium dichromate.^11aThis revised C(11) inversion

protocol offers slight improvement over the previous

sequence in terms of yield, delivering 14 in five steps and

42% overall yield from compound 8. Nevertheless, a more

satisfying protocol for accomplishing the C(11) carbinol

inversion was still needed, and was ultimately developed

(vide infra).

at C(6) was expected to provide pyranone 6.¹⁹The lower

pK_aof the C(8) proton precluded such an alkylation,

however, as quenching of the enolate derived from ketone

19 with deuterium oxide resulted in exclusive deuterium

incorporation at C(8). This result made clear that the

desired alkyl chain must be present during the ring

expansion step.

In light of these results, a new strategy was devised

that involved addition of an R-alkoxy carbanion to lactone

14 followed by subsequent mesylation and pinacol rear-

rangement to achieve the ring expansion with the

requisite 3-butenyl group in place. We envisioned that

transmetalation of an R-alkoxyorganostannane would

generate a lithium reagent that would be suitable for this

task. Accordingly, the racemic R-alkoxyorganostannane

rac-21 was prepared as shown in Scheme 7. Addition of

tributylstannyl anion to 4-pentenal²⁰provided the R-hy-

droxystannane rac-20 as described by Still and co-

workers.²¹This adduct was remarkably stable for a

compound of its type and could be subjected to silica gel

chromatography without significant decomposition. Pro-

tection of rac-20 with R-chloroethyl ethyl ether provided

the ethoxyethyl-protected R-alkoxystannane rac-21 as an

inseparable mixture of four stereoisomers. This com-

pound, unlike the free alcohol, suffered severe decompo-

sition on silica gel. Fortunately, purification was possible

using silica gel that had been saturated with triethyl-

amine.

Transmetalation of rac-21 with n-BuLi provided the

corresponding lithium reagent, to which 14 was added

at low temperature.²¹Following acidic hydrolysis of the

ethoxyethyl protecting groups, diols 22a and 22b were

isolated, and the desired diol 22a was selectively mesy-

lated to provide 23. The correct C(6) epimer of pyranone

6 was expected to be formed upon stereospecific rear-

rangement of this diastereomer. The undesired diaste-

reomer 22b was recycled to 14 via oxidative cleavage with

periodic acid. An alternative to recycling 22b that was

explored was the direct conversion of 22b to 22a via C(6)

At hand now was the task of achieving ring expansion

of lactone 14 to establish the B ring, with appropriate

substitution at C(6) to provide an entry to the A ring.

After unsuccessfully attempting to accomplish both goals

in a single step through the use of halolithium carbenoid

chemistry,^10a,b,17the OH insertion of a metallocarbenoid

was investigated. As shown in Scheme 6, treatment of

lactone 14 with the diazolithium reagent 17¹⁸provided

the diazoketone intermediate 18, which subsequently

underwent OH insertion in the presence of rhodium(II)

to give ketone 19. Enolate formation and homoallylation

(17) (a) Taguchi, H.; Yamamoto, H.; Nozaki, H. Bull. Chem. Soc.

J pn. 1977, 50, 1592-1595. (b) Barluenga, J .; Llavona, L.; Yu, M.;

Concellon, J . M. Tetrahedron 1991, 47, 7875-7886 and references cited

within.

(18) For recent reviews on the utility of diazo compounds, see: (a)

Smith, A. B., III; Dieter, R. K. Tetrahedron 1981, 37, 2407-2439. (b)

Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733-749. (c) Regitz,

M. Synthesis 1972, 351-373. (d) Kruglaya, O. A.; Vyazankin, N. S.

Russ. Chem. Rev. 1980, 49, 357-370. For reactions of R-silyldiazo-

methane, see: (e) Schollkopf, U.; Scholz, H.-U. Synthesis 1976, 271-

272. (f) Martin, M. Synth. Commun. 1983, 13, 809-811. (g) Heslin, J .

C.; Moody, C. J . J . Chem. Soc., Perkin Trans. 1 1988, 1417-1423. (h)

Moody, C. J .; Taylor, R. J . J . Chem. Soc., Perkin Trans. 1 1989, 721-

731. (i) Davies, M. J .; Heslin, J . C.; Moody, C. J . J . Chem. Soc., Perkin

Trans. 1 1989, 2473-2484. (j) Davies, M. J .; Moody, C. J .; Taylor, R.

J . Synlett 1990, 93-94. (k) Davies, M. J .; Moody, C. J . Synlett 1990,

95-96.

(19) For reviews on alkylation of carbonyl compounds, see: (a) Reetz,

M. T. Angew. Chem., Int. Ed. Engl. 1982, 21, 96-108. (b) Whitesell, J .

K.; Whitesell, M. A. Synthesis 1983, 517-536.

(20) Whittaker, M.; McArthur, C. R.; Leznoff, C. C. Can. J . Chem.

1985, 63, 2844-2852.

(21) Still, W. C. J . Am. Chem. Soc. 1978, 100, 1481-1486.

4074 J . Org. Chem., Vol. 65, No. 13, 2000

Burke et al.

with (R)-BINAL²³provided the hydroxystannane (S)-20

in 86% enantiomeric excess as determined by H NMR

Sch em e 7

1

analysis of the Mosher ester derived from (R)-(+)-

methoxytrifluoromethylphenylacetic acid. Subsequent

protection of (S)-20 with R-chloroethyl ethyl ether pro-

vided 6(S)-21 and 6(R)-21 in 84% and 14% yields,

respectively. Treatment of lactone 14 with the lithium

reagent derived from 6(S)-21 under the same conditions

employed for rac-21 above delivered the desired diol 22a

in 70% yield along with 5% of the undesired 22b. As a

practical matter, acyl stannane 24 proved difficult to

handle on a large scale owing to its rapid decomposition

in the presence of oxygen to the corresponding tin

carboxylate.²²As a result, rac-21 has remained the

R-alkoxystannane reagent of choice due to the relative

ease with which it can be prepared.

Ring expansion of the five-membered hemiacetal moi-

ety of 23 was now needed to establish the B-ring. Several

reagents were surveyed for their ability to promote a

pinacol rearrangement of hydroxy mesylate 23. Lewis

acidic promoters such as triethylaluminum and diethyl-

aluminum chloride, which were reported to be effective

promoters of pinacol rearrangements of vicinal hydroxy

mesylates,²⁴were incompatible with the acid-sensitive

functionality present in our system. As depicted in

Scheme 9, we found that ethylmagnesium bromide²⁵

promoted the desired ring expansion, possibly proceeding

through the seven-membered cyclic transition state

shown,²⁴to give the pyranone 6. However, the furanyl

ketone 25 also forms under these conditions, presumably

resulting from direct displacement of the mesylate by the

hemiacetal alkoxide with a resultant rearrangement of

the unstable epoxide via a 1,2-hydride shift. We at-

tempted to suppress the formation of free alkoxide that

was thought to be responsible for the observed side

reaction by adding anhydrous MgBr₂to the reaction

mixture, but no change in the product ratio was observed.

Sch em e 8

(23) (a) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J . Am.

Chem. Soc. 1984, 106, 6709-6716. (b) Noyori, R.; Tomino, I.; Yamada,

M.; Nishizawa, M. J . Am. Chem. Soc. 1984, 106, 6717-6725.

(24) For examples using aluminum reagents, see: (a) Suzuki, K.;

Katayama, E.; Tsuchihashi, G. Tetrahedron Lett. 1983, 24, 4997-5000.

(b) Suzuki, K.; Katayama, E.; Tsuchihashi, G. Tetrahedron Lett. 1984,

25, 1817-1820. (c) Suzuki, K.; Katayama, E.; Matsumoto, T.; Tsuchi-

hashi, G. Tetrahedron Lett. 1984, 25, 3715-3718. (d) Tsuchihashi, G.;

Tomooka, K.; Suzuki, K. Tetrahedron Lett. 1984, 25, 4253-4256. (e)

Suzuki, K.; Ohkuma, T.; Tsuchihashi, G. Tetrahedron Lett. 1985, 26,

861-864. (f) Suzuki, K.; Tomooka, K.; Matsumoto, T.; Katayama, E.;

Tsuchihashi, G. Tetrahedron Lett. 1985, 26, 3711-3714. (g) Suzuki,

K.; Tomooka, K.; Shimazaki, M.; Tsuchihashi, G. Tetrahedron Lett.

1985, 26, 4781-4784. (h) Suzuki, K.; Ohkuma, T.; Miyazawa, M.;

Tsuchihashi, G. Tetrahedron Lett. 1986, 27, 373-376. (i) Schoenen,

F. J .; Porco, J . A., J r.; Schreiber, S. L.; VanDuyne, G. D.; Clardy, J .;

Tetrahedron Lett. 1989, 30, 3765-3768. For examples using other

acids, see: (j) Kakimoto, M.; Seri, T.; Imai, Y. Bull. Chem. Soc. J pn.

1988, 61, 2643-2644. (k) Harada, T.; Mukaiyama, T. Chem. Lett. 1992,

81-84. (l) Kudo, K.; Saigo, K.; Hashimoto, Y.; Saito, K.; Hasegawa,

M. Chem. Lett. 1992, 1449-1452. (m) Paquette, L. A.; Lawhorn, D.

E.; Teleha, C. A. Heterocycles 1990, 30, 765-769. (n) Paquette, L. A.;

Lord, M. D.; Negri, J . T. Tetrahedron Lett. 1993, 34, 5693-5696. (o)

Paquette, L. A.; Branan, B. M.; Friedrich, D.; Edmonson, S. D.; Rogers,

R. D. J . Am. Chem. Soc. 1994, 116, 506-513.

carbinol inversion. One-step inversion protocols failed to

achieve inversion at this center, and reduction of the C(6)

ketone derived from 22b with a variety of reductants

returned the unwanted diol diastereomer 22b as the

major product.

Originally, an R-alkoxystannane derived from an enan-

tiomerically enriched R-hydroxystannane was used to

avoid the formation and recycling of 22b (Scheme 8).^8b

Reaction of tributylstannylmagnesium chloride with 2

equiv of 4-pentenal provided acyl stannane 24²²via a

Cannizarro-type reaction. Asymmetric reduction of 24

(25) (a) Gilchrist, T. L.; Stanford, J . E. J . Chem. Soc., Perkin Trans.

1 1987, 225-230. (b) Sisti, A. J . J . Org. Chem. 1968, 33, 453. (c) Sisti,

A. J .; Vitale, A. C. J . Org. Chem. 1972, 37, 4090-4094. (d) Corey, E.

J .; Ohno, M.; Vatakencherry, P. A.; Mitra, R. B. J . Am. Chem. Soc.

1961, 83, 1251-1253. (e) Brook, P. R. J . Chem. Soc., Chem. Commun.

1968, 565-567. (f) Suga, T.; Hirata, T.; Shishibori, T.; Matsuura, T.

Tetrahedron Lett. 1968, 5553-5555. For

a review on the pinacol

(22) (a) Chan, P. C.-M.; Chong, J . M. J . Org. Chem. 1988, 53, 5584-

5586. (b) Chong, J . M.; Mar, E. K. Tetrahedron 1989, 45, 7709-7716.

(c) Chong, J . M.; Mar, E. K. Tetrahedron Lett. 1990, 31, 1981-1984.

(d) Chan, P. C.-M.; Chong, J . M. Tetrahedron Lett. 1990, 31, 1985-

1988. (e) Kosugi, M.; Naka, H.; Sano, H.; Migita, T. Bull. Chem. Soc.

J pn. 1987, 60, 3462-3464.

rearrangement, see: (g) Rickborn, B. In Comprehensive Organic

Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: London, 1991;

Vol. 3, pp 721-732. For studies of migratory aptitude, see: h)

Nakamura, K.; Osamura, Y. Tetrahedron Lett. 1990, 31, 251-254. (i)

Collins, C. J . J . Am. Chem. Soc. 1955, 77, 5517-5523. (j) Witsuba, E.;

Ruchart, C. Tetrahedron Lett. 1981, 22, 4069-4072.

Halichondrin B: Synthesis of the C(1)-C(15) Subunit

J . Org. Chem., Vol. 65, No. 13, 2000 4075

Sch em e 9

Sch em e 10

Sch em e 11

Changing the leaving group from mesylate to chloride

and subjection of the chlorohydrin to the reaction condi-

tions resulted in exclusive formation of 25. Thermolysis

of the mesylate in the presence of triethylamine in

refluxing toluene also provided 25 as the sole product.

Ironically, the mesylate 26 derived from diol 22b

smoothly undergoes EtMgBr-induced pinacol rearrange-

ment to give 27, the C(6) epimer of pyranone 6, in high

yield (Scheme 10). Unfortunately, C(6) epimerization of

this product to provide 6 could not be achieved under a

variety of conditions, presumably due again to preferred

enolization toward C(8).

Despite the low yields of the R-alkoxyorganostannane

addition and pinacol rearrangement steps, we had met

our goals of effecting ring expansion to install the B-ring

while establishing the correct stereochemistry at C(6).

At this point, we decided to direct our efforts at comple-

tion of the A-ring. We envisioned that stereoselective

reduction of ketone 6 from the R-face followed by an

alkoxypalladation/carbonylation procedure²⁶would com-

plete construction of the dioxadecalin AB-ring system

with appropriate substitution at C(3). Reduction at C(7)

with DIBALH delivered the alcohol 28 of desired stereo-

chemistry in nearly quantitative yield (Scheme 11). The

use of Luche conditions or Zn(BH₄)₂gave the same

stereochemical outcome, albeit in lower yield (ca. 70%).

Unfortunately, subjection of 28 to the alkoxypalladation/

carbonylation conditions resulted in decomposition, forc-

ing us to employ a different method for effecting A-ring

closure.

We anticipated that A-ring installation might be real-

ized by an intramolecular Michael addition of the C(7)

hydroxyl with an enoate generated by Wittig homologa-

tion at C(3). Accordingly, ozonolysis of 28 and Wittig

reaction with the resultant C(3) hemiacetal (in brackets)

afforded enoate 29 (Scheme 11). Having established the

requisite Michael acceptor and donor functionalities, we

(26) (a) Semmelhack, M. F.; Budurow, C. J . Am. Chem. Soc. 1984,

106, 1496-1498. (b) Semmelhack, M. F.; Kim, C. R.; Dobler, W.; Meier,

M. Tetrahedron Lett. 1989, 30, 4925-4928. (c) Semmelhack, M. F.;

Bodurow, C.; Baum, M. Tetrahedron Lett. 1984, 25,. 3171-3174.

4076 J . Org. Chem., Vol. 65, No. 13, 2000

Burke et al.

Sch em e 12

Sch em e 13

turned our attention to the conjugate addition step.

Treatment of 29 with benzyltrimethylammonium meth-

oxide in benzene at 5 °C followed by warming to 18 °C

for 3 h provided the desired C(3) equatorial adduct 30

as the sole product. The starting material was consumed

within 10 min at 5 °C but gave a roughly equimolar

mixture of axial and equatorial C(3) epimers after this

time. The prolonged reaction time and increased tem-

perature are required to facilitate equilibration via a

retro-Michael/Michael addition pathway to the more

stable equatorial isomer. It is noteworthy that a 1:1

mixture of C(3) epimeric adducts was isolated upon

conducting the reaction in methanol at room tempera-

ture. This result illustrates the dramatic effect that

reaction media can exert upon thermodynamic equilibria.

This completed the AB-ring system with all stereocenters

correctly set.

The problems attending overreduction during the

inversion of the C(11) carbinol center in our first-

generation approach prompted us to develop an inversion

plan that could be effected later in the synthesis. For this

second-generation approach, we envisioned that the

caged compound 3 would arise from compound 30 as

before (Scheme 12). However, compound 30 would now

be prepared by inversion of its C(11) epimer 31 via an

oxidation-reduction sequence. With the lactone func-

tionality absent, it was hoped that the more robust

methyl ester that would now be present during the C(11)

inversion sequence would survive the reduction step. It

was anticipated that compound 31 could also be prepared

from R-^D-glucoheptonic acid γ-lactone 7 in a manner

analogous to that described above, with deferral of the

C(11) carbinol inversion until late in the sequence.

Protection of 8 as its TBDMS ether provided lactone

32 (Scheme 13). Addition of the organolithium species

derived from the racemic ethoxyethyl-protected alkoxy-

stannane rac-21 followed by acidic hydrolysis provided

a separable mixture of diols 33a and 33b. The unwanted

diol diastereomer 33b was recycled to 32 by oxidative

cleavage with periodic acid. Mesylation of 33a afforded

34, which was then subjected to the ethylmagnesium

bromide-promoted pinacol rearrangement to give pyra-

none 35 as well as the undesired furanyl ketone 36 via

pathways related to those shown in Scheme 9 for the

series of compounds epimeric at C(11). In converting 33a

to mesylate 34, considerable decomposition of the product

occurred at prolonged reaction times, thus the reaction

was arrested early to provide 64% of 34 with 17% of 33a

being recovered. That this was not a problem in the

conversion of 22a to 23 suggests that the remote C(11)

stereocenter imparts a significant effect upon the relative

stabilities of mesylates 34 and 23.

Reduction of the pyranone 35 with DIBALH was

followed by ozonolysis and Wittig homologation at C(3)

to afford the enoate 37 as an inseparable 12:1 mixture

of (E) and (Z) isomers (Scheme 14). Base-catalyzed

intramolecular Michael addition yielded a mixture of C(3)

epimers which, upon equilibration for 3 h at room

temperature, gave the desired thermodynamic adduct 31

as the sole product.

With the dioxadecalin AB-ring system now in place via

the revised route, inversion at C(11) of 31 and correlation

of the inverted TBDMS ether with compound 30 was

pursued. Deprotection of 31 with TBAF afforded the

alcohol 38 (Scheme 14). Several oxidants were screened

for the conversion of this alcohol to ketone 39. PCC

provided the desired ketone in poor yield along with

lactone 40, a side product resulting from oxidative

cleavage of the C(10)-C(11) bond. Use of the Dess-

Martin periodinane resulted in only 15% conversion after

several days of stirring at room temperature. Fortu-

nately, we found that treatment of 38 with TPAP/NMO¹²

in CH₂Cl₂delivered 39 in high yield. The success of this

Halichondrin B: Synthesis of the C(1)-C(15) Subunit

J . Org. Chem., Vol. 65, No. 13, 2000 4077

Sch em e 14

F igu r e 2. Rationalization of chelation-controlled reduction

outcome.

The outcome of this chelation-directed reduction may

be rationalized as shown in Figure 2. There are two

possible five-membered zinc chelates involving the ketone

carbonyl. Chelation at the more sterically encumbered

pentylidene ketal oxygen would favor â-face attack of

hydride and the undesired (R) stereochemistry at C(11).

The desired (S) isomer 41 of the product alcohol, experi-

mentally favored by a 14:1 ratio, results from R-face

delivery of hydride, apparently involving the chelate with

the less hindered ether oxygen of the B-ring. No products

arising from reduction of the methyl ester moiety were

observed under these conditions. Luche conditions (NaBH₄/

CeCl₃‚7H₂O)¹⁶resulted in a nearly equimolar mixture of

C(11) epimers. Use of Zn(BH₄)₂in benzene or diethyl

ether instead of pentane gave comparable yields but

poorer selectivity, the worst of which (ca. 4:1 41:38) was

observed with diethyl ether. Selectivity improved in

benzene upon lowering the concentration, presumably

due to the dilution of the diethyl ether used to transfer

the hydride reagent. We believe the reason for these

trends is that less polar solvents compete less effectively

with the substrate for zinc binding. A Lewis-basic solvent

such as diethyl ether can competitively bind zinc ions

present in solution, thereby leaving a considerable frac-

tion of substrate uncoordinated to zinc. Competing reduc-

tion of the uncomplexed substrate would proceed with

no chelation-controlled stereoselectivity.

Our second-generation C(11) inversion sequence signi-

fies a marked improvement over our first-generation

protocol, as summarized in Figure 3. The late-stage

inversion strategy delivers the TBS ether 30 of desired

C(11) stereochemistry in three steps and 59% overall

yield from the alcohol 38. By avoiding the problem of

overreduction, the number of steps in the inversion

sequence is reduced by two and the overall yield is

improved by 17%.

With a more satisfactory route to compound 30 now

in hand, it remained to install the polycyclic CDE ring

system and complete the synthesis of the C(1)-C(15)

subunit 3. Selective removal of the terminal pentylidene

acetal^9,27of 30 was followed by oxidative cleavage of the

resulting diol with periodate to afford aldehyde 5 (Scheme

oxidation is auspicious, given the fact that the C(11)

oxidation step in our first-generation synthesis was the

lowest yielding reaction in the sequence.

With ketone 39 now in hand, a chelation-controlled

reduction with Zn(BH₄)₂was attempted; this reagent had

provided the correct C(11) epimer from the simpler

ketone 11 in our first-generation synthesis. Treatment

of 39 with Zn(BH₄)₂in pentane at room temperature gave

1

an inseparable 14:1 mixture (as determined by H NMR

spectroscopy) of C(11) epimers, favoring the desired (S)

alcohol 41, in good yield. The use of Zn(BH₄)₂, which had

proven troublesome in large-scale applications in the

first-generation sequence, is not a problem here due to

the smaller quantities of material involved. Thus, an

obvious advantage of performing this step later in the

sequence is that there are fewer steps to follow, thereby

lessening the need to generate the reduction product in

large quantities. The product obtained from TBDMS

protection of 41, which was separable from the small

amount of silyl ether 31 that was also formed during this

step, was shown to be the desired compound 30, identical

in all respects to that prepared by the other sequence.

(27) Haines, A. H. Adv. Carbohydr. Chem. Biochem. 1981, 39, 13-

70.

4078 J . Org. Chem., Vol. 65, No. 13, 2000

Burke et al.

Sch em e 16

F igu r e 3. Comparison of C(11) carbinol inversion protocols.

Sch em e 15

of 5 provided sound evidence that the desired trans AB-

ring junction had been successfully installed. Homolo-

gation to the benzyloxymethyl enone 4 was accomplished

by Wittig reaction of 5 with [R-(benzyloxy)acetyl]meth-

ylenetriphenylphosphorane (42)²⁸in refluxing toluene.

High temperature was required for this reaction since

no conversion was observed at room temperature or in

refluxing THF. The (E)-enone 4 was isolated in quantita-

tive yield, containing all of the functionality necessary

to effect the cage formation cascade.

It was hoped that the caged ketal moiety could be

established by simply subjecting compound 4 to acidic

conditions in the presence of fluoride ion. In the event,

treatment of enone 4 with 52% aqueous HF in acetonitrile

(1:10 v/v) at high dilution (0.01 M) assembled the

polycyclic CDE ring system in 3 via a sequence of four

in situ reactions illustrated in Scheme 15. Removal of

the TBS and fused pentylidene acetal protecting groups

precedes Michael addition of the C(9) hydroxyl to the

enone, and the endo Michael adduct (shown) undergoes

acetal formation at C(14) with the remaining C(8) and

C(11) hydroxyls.

An intriguing, unanticipated side product that typically

forms to the extent of 30-40% in this reaction is the

methyl ketone 43, in which the benzyloxy group has been

lost (Scheme 16). Presumably, generation of the extended

enol followed by elimination of benzyl alcohol, tautomer-

ization of the resulting enol to the enone, and Michael

addition gives 43. The low and variable yields of 3 from

4 in this elaborate step can be attributed in large part to

this side reaction.

15). The TBS ether was prone to cleavage under the

acidic conditions required to hydrolyze the terminal

pentylidene ketal and so the reaction had to be arrested

prior to complete conversion. With the loss of the C(13)

carbon, oxidation at C(12) to give an aldehyde, and the

loss of one pentylidene ketal, ¹H NMR analysis of

compound 5 was simplified relative to many of its

precursors. Therefore, we chose to verify the trans

stereochemistry about the dioxadecalin AB-ring system

at this stage. The three-bond coupling constant of 10.2

Hz that was observed between the H(6) and H(7) protons

(28) (a) Bestmann, H. J .; Arnason, B. Chem. Ber. 1962, 95, 1513-

1527. (b) Bestmann, H. J . Tetrahedron Lett. 1960, 7-9. (c) Bestmann,

H. J .; Arnason, B. Tetrahedron Lett. 1961, 455-457. (d) Chopard, P.

A.; Searle, R. J . G.; Devitt, F. H. J . Org. Chem. 1965, 30, 1015-1019.

(e) Ramirez, F.; Dershowitz, S. J . Org. Chem. 1957, 22, 41-45.

Halichondrin B: Synthesis of the C(1)-C(15) Subunit

J . Org. Chem., Vol. 65, No. 13, 2000 4079

Ta ble 1. Selected ¹H NMR Da ta for Ca ged Keta l Segm en ts of Ha lich on d r in B^a

position

2

Burke (R ) CH₂OBn)

Salomon^6b(R ) CH₂OBn)

Kishi^4b(R ) (CH₂)₄CH₃)

halichondrin B^1a

2.41 (dd, J ) 15.8, 5.0)

2.49 (dd, J ) 15.8, 8.1)

3.81 (m)

2.41 (dd, J ) 15.8, 5.1)

2.49 (dd, J ) 15.8, 7.8)

3.8 (m)

2.45 (dd, J ) 15.8, 5.1)

2.52 (dd, J ) 15.8, 7.6)

3.81 (m)

2.44 (dd, J ) 16.5, 3.0)

2.57 (dd, J ) 16.5, 9.3)

3.88 (m)

3

4 and 5

6

7

8

1.33, 1.73, 1.41, 2.04 (m)

4.25 (ddd, J ) 10.0, 9.6, 4.4) 4.25 (ddd, J ) 10, 9.6, 4.6)

1.3-1.4, 1.74, 1.3-1.4, 2.04 (m) 1.40, 1.80, 1.40, 2.05 (m)

1.35, 1.75, 1.41, 2.04 (m)

4.29 (ddd, J ) 10.0, 9.6, 4.3) 4.33 (ddd, J ) 9.3, 9.3, 4.0)

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)

2.97 (dd, J ) 9.6, 4.6)

4.39 (dd, J ) 3.9, 1.8)

4.14 (dd, J ) 6.5, 3.9)

4.21 (dd, J ) 6.5, 4.6)

4.65 (dd, J ) 4.5, 4.5)

4.72 (dd, J ) 4.6, 4.6)

1.98 (d, J ) 13.4)

2.96 (dd, J ) 9.6, 1.9)

4.33 (dd, J ) 4.1, 1.9)

4.11 (dd, J ) 6.6, 4.1)

4.17 (dd, J ) 6.6, 4.6)

4.58 (dd, J ) 4.6, 4.4)

4.67 (dd, J ) 4.7, 4.4)

1.98 (dd, J ) 13.3, 4.7)

2.03 (d, J ) 13.3)

2.98 (dd, J ) 9.3, 2.4)

4.31 (dd, J ) 3.6, 2.4)

4.13 (dd, J ) 6.0, 3.6)

4.18 (dd, J ) 6.0, 4.5)

4.60 (dd, J ) 4.5, 4.5)

4.71 (dd, J ) 4.5, 4.5)

1.98 (dd, J ) 12.6, 4.5)

2.09 (d, J ) 12.6)

9

10

11

12

13

2.24 (dd, J ) 13.4, 5.0)

2.24 (dd, J ) 13.4, 5.1)

a

Chemical shifts are reported in ppm relative to the TMS signal. Coupling constants (in parentheses) are reported in Hz.

Sch em e 17

F igu r e 4. Caged ketal substructure.

caged product 46 and instead gave the furan 47 in good

yields (47-85%). Apparently, the initial Michael adduct

can either undergo acetalization to form the caged ketal

or can equilibrate via a retro-Michael addition to the (E)-

and (Z)-enones, of which the latter can undergo cycliza-

tion with the C(11) hydroxyl, giving rise to a cyclic

hemiacetal which eliminates water to give furan 47. The

absence of the inductively withdrawing ketone R-alkoxy

substituent likely disfavors both Michael addition and

ketalization relative to 4, thereby promoting the retro-

Michael process that leads ultimately to 47. The compet-

ing equilibria possible for 4 and 45 leading to 3, 43 and

47 illustrate how subtle structural changes can greatly

influence complex reaction pathways. Although the elabo-

rate transformation of 4 to the caged ketal 3 was

accomplished, more options must be explored in order to

suppress the unwanted side reactions and increase the

yield of caged product comprising the ABCDE ring

system of halichondrin B.

1

We were able to compare the H and ¹³C NMR data

we obtained for 3 with reported data for other relevant

caged ketal-containing compounds, including halichon-

drin B (Figure 1),^1aKishi’s model system 48,^4band

Salomon’s model system^6bwith the same reported struc-

ture as 3. The caged ketal substructure common to all of

these compounds is shown in Figure 4. All of the data,

Accordingly, we attempted to modify the Michael

shown in Tables 1 and 2, correlate well with the exception

acceptor to avoid side reactions of this type. The homo-

of the chemical shifts and multiplicities of the C(13)

allyl enone 45 was obtained by reaction of Wittig reagent

44 with aldehyde 5 (Scheme 17). Although this Michael

acceptor avoids the problem of elimination described

above for 4, an alternative side reaction occurs in this

case. Subjection of 45 to various conditions, including

aqueous HF in acetonitrile, failed to provide the desired

protons. The neighboring aromatic group, present in our

segment (and Salomon’s), is the likely cause of the

deviation from the observed resonances in halichondrin

B and 48. Our data (and Salomon’s) show a doublet for

the signal at δ 1.98 and a doublet of doublets for the

signal at δ 2.24. The data for Kishi’s model system 48

4080 J . Org. Chem., Vol. 65, No. 13, 2000

Burke et al.

Ta ble 2. Selected ¹³C NMR Da ta for Ca ged Keta l

Segm en ts of Ha lich on d r in B^a

µm layer thickness). Preparative TLC was carried out using

0.5 and 2.0 mm × 10 cm × 10 cm E. Merck precoated silica

gel 60 (60 F₂₅₄) plates. TLC visualization was accomplished

using either a UV lamp, iodine adsorbed on silica gel, or

charring solution [p-anisaldehyde (PAA), phosphomolybdic

acid (PMA)]. Flash column chromatography (FCC) was done

according to the procedure by Still²⁹on EM Science silica gel

60 (230-400 mesh) or Florisil (100-200 mesh) purchased from

Aldrich.

Tetrahydrofuran (THF), diethyl ether (Et₂O), and benzene

were distilled from sodium/benzophenone ketyl. Toluene

(PhCH₃) was distilled from sodium metal. Triethylamine

(Et₃N), pyridine, dichloromethane (CH₂Cl₂), and acetonitrile

(CH₃CN) were distilled from calcium hydride. Dimethyl sul-

foxide (DMSO) and N,N-dimethylformamide (DMF) were

distilled under reduced pressure from calcium hydride and

stored over 4 Å molecular sieves. Deuteriochloroform (chloro-

form-d; CDCl₃), deuterioacetone (acetone-d₆), and deuterioben-

zene (benzene-d₆; C₆D₆) were stored over 4 Å molecular sieves

before use. Deuteriomethanol (methanol-d₄) was used as

received from Aldrich in glass ampules. Methanesulfonyl

chloride (MsCl) was distilled under reduced pressure prior to

use. Methanol (MeOH) was distilled from magnesium meth-

oxide. Hexanes were distilled at atmospheric pressure. All

other commercially obtained reagents and solvents were used

as received without further purification unless indicated

otherwise.

position

Burke (R ) CH₂OBn)

halichondrin B^1a

1

2

3

173.3

41.1

75.1

172.8

41.2

74.9

4

5

6

7

8

9

10

11

12

13

14

69.6

79.3

76.0

76.6

78.0

83.9

82.1

44.9

110.9

69.6

79.1

75.8

73.3

78.0

83.8

82.5

49.4

111.3

a

Chemical shifts are reported in ppm relative to the center line

of the CDCl₃signal.

and halichondrin B show the opposite, with the upfield

signal appearing as a doublet of doublets and the down-

field signal appearing as a doublet. This reflects either a

chemical shift anisotropy effect on both C(13) protons^6b

or (less probably) a conformational change stemming

from the nature of the group appended to C(14).

P r ep a r a tion of Alcoh ol 8. To a cloudy suspension of R-^D-

glucoheptonic acid γ-lactone (7) (30 g; 0.14 mol) in 3-pentanone

(1.6 L; 0.088 M) was added concentrated sulfuric acid in

dropwise fashion (30 mL; 0.56 mol; 4 equiv). The mixture was

stirred at room temperature for 3 d after which time it was

poured into cold distilled water (200 mL). The aqueous layer

was extracted with Et₂O. The combined organic layers were

washed with saturated NaHCO₃and dried over MgSO₄.

Filtration and evaporation of solvents in vacuo gave a brown

oil. Flash column chromatography (2:1 to 1:1 hexanes-Et₂O,

then Et₂O) gave the desired alcohol 8 as colorless plates (19.7

g; 0.0573 mol; 39%) and the monoprotected acetal 9 as a sticky

colorless oil (15.9 g; 0.0576 mol; 39%). Triol 9 was resubjected

to the reaction conditions to provide an additional 7.7 g of 8

for a total of 27.4 g (0.0797 mol; 55%). Data for 8: R_f0.59

Con clu sion

A short (14-16 step), efficient synthesis of the C(1)-

C(15) ABCDE ring system of halichondrin B has been

developed from the inexpensive carbohydrate R-^D-gluco-

heptonic acid γ-lactone (7), possessing the desired C(8),

C(9), and C(10) structural features. To enable the em-

ployment of this starting material, two protocols have

been developed for carbinol inversion at C(11), one early

and one late in the synthetic sequence, with the latter

having substantial practical advantages. Key ring form-

ing reactions include a Mg²⁺-catalyzed pinacol ring

expansion, an intramolecular Michael addition, and a

one-pot multistep cage-forming reaction cascade. Further

studies of subunit synthesis and coupling leading to the

total synthesis of halichondrin B are currently in progress.

(Et₂O); mp 74-77 °C; [R]²⁴-46.9° (c 1.17, CHCl₃); IR (thin

D

film) 3520 (br), 1785 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 0.86-

0.96 (m, 12 H), 1.58-1.78 (m, 8 H), 3.26 (br s, OH), 3.87-3.99

(m, 2 H), 4.07-4.13 (m, 2 H), 4.58 (t, J ) 3.5 Hz, 1 H), 4.86 (d,

J ) 5.4 Hz, 1 H), 4.92 (dd, J ) 5.4, 3.5 Hz, 1 H); ¹³C NMR (75

MHz, CDCl₃) δ 7.50 (CH₃), 7.93 (CH₃), 8.09 (CH₃), 28.69 (CH₂),

29.23 (CH₂), 29.29 (CH₂), 67.60 (CH₂), 71.41 (CH), 74.81 (CH),

76.47 (CH), 77.09 (CH), 78.23 (CH), 113.44 (C), 118.63 (C),

173.15 (C); HRMS calcd for C₁₅H₂₃O₇(M⁺- C₂H₅) 315.1444,

found 315.1436.

Exp er im en ta l Section

Gen er a l Meth od s. Melting points (mp) are uncorrected.

Optical rotations were measured on a digital polarimeter;

concentrations (c) are reported in g/100 mL. Infrared (IR)

spectra are reported in wavenumbers (cm^-1) with broad signals

denoted by (br). Proton nuclear magnetic resonance (¹H NMR)

spectra were recorded at 300 MHz in deuterated solvents.

Carbon-13 nuclear magnetic resonance (¹³C NMR) spectra

were recorded at 75 MHz. ¹³C NMR spectral assignments were

aided by distortionless enhancement by polarization transfer

(DEPT) experiments with a phase angle of 135°: (C) not

observed; (CH) positive; (CH₂) negative; (CH₃) positive. Mass

spectra (MS) were obtained using electron impact (EI) at 70

eV with peak matching. Fast atom bombardment MS (FAB)

were obtained on a VG Analytical ZAB-2F mass spectrometer

(Ion Tech FAB gun, 8 kV, Xe carrier gas) or a Kratos MS 50

(primary beam was 1 mA of 7kV Xe carrier gas, 8 kV ion

acceptation voltage).

All moisture-sensitive reactions were performed in flame-

dried glassware under a stream of nitrogen, unless indicated

otherwise. Bath temperatures were used to record the reaction

temperature in all cases. All reactions were stirred magneti-

cally unless otherwise indicated. When prolonged cooling was

necessary, an immersion cooler was employed. Analytical thin-

layer chromatography (TLC) was carried out on E. Merck

(Darmstadt) TLC plates precoated with silica gel 60 F₂₅₄(250

P r ep a r a tion of Keton e 11. To a slurry of freshly prepared

Dess-Martin periodinane (147 mg; 0.347 mmol; 1.1 equiv) in

CH₂Cl₂(2.5 mL; 0.14 M) was added alcohol 8 (105 mg; 0.305

mmol) in CH₂Cl₂(2.5 mL; 0.061 M in 8). The solution became

completely homogeneous after stirring for 10 min at room

temperature and was quenched with saturated NaHCO₃(10

mL). The layers were partitioned, and the aqueous layer was

extracted with CH₂Cl₂. The combined organic layers were

washed with 0.5 N NaOH to remove periodinane byproducts,

dried over MgSO₄, filtered, and concentrated in vacuo to give

ketone 11 as a colorless oil (102 mg; 0.298 mmol; 98%). Data

for 11: R_f0.33 (1:2 hexanes-Et₂O); [R]²⁴+44.3° (c 1.11,

D

1

CHCl₃); IR (thin film) 1775, 1730 cm^-1; H NMR (300 MHz,

CDCl₃) δ 0.77-0.98 (m, 12 H), 1.56-1.81 (m, 8 H), 3.96 (t, J

) 7.9 Hz, 1 H), 4.28 (t, J ) 7.9 Hz, 1 H), 4.66 (t, J ) 7.9 Hz,

1 H), 4.88 (d, J ) 5.9 Hz, 1 H), 5.25 (dd, J ) 5.9, 4.6 Hz, 1 H),

5.40 (d, J ) 4.6 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ 7.18

(CH₃), 7.59 (CH₃), 7.65 (CH₃), 8.12 (CH₃), 27.55 (CH₂), 28.68

(CH₂), 29.14 (CH₂), 29.21 (CH₂), 65.78 (CH₂), 75.69 (CH), 76.25

(29) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-

2925.

Halichondrin B: Synthesis of the C(1)-C(15) Subunit

J . Org. Chem., Vol. 65, No. 13, 2000 4081

(CH), 79.12 (CH), 81.57 (CH), 114.96 (C), 118.72 (C), 172.77

(C), 199.13 (C); HRMS calcd for

313.1287, found 313.1290.

(CH₃), 29.36 (CH₂), 29.69 (CH₂), 29.84 (CH₂), 66.56 (CH₂), 70.83

(CH), 75.89 (CH), 75.96 (CH), 78.65 (CH), 78.80 (CH), 112.32

C

₁₅H₂₁O₇(M⁺- C₂H₅)

(C), 118.20 (C), 173.30 (C); HRMS calcd for C₂₃H₄₁O₇Si (M⁺

H) 457.2621, found 457.2597.

-

P r ep a r a tion of Alcoh ol 13 fr om 11. Freshly prepared Zn-

(BH₄)₂(0.16 M in Et₂O, 5.0 mL, 0.80 mmol) was added

dropwise at -78 °C under nitrogen to a solution of ketone 11

(840 mg, 2.46 mmol) in dry Et₂O (10 mL) over 6 min. The clear

solution was stirred at -78 °C for 1 h, and stirring was

continued at -50 °C for 2.5 d. The reaction was quenched

slowly with 0.6 N HCl (10 mL) and then warmed to room

temperature. The biphasic solution was poured into 0.6 N HCl

(10 mL) and extracted with Et₂O. The extract was neutralized

with saturated NaHCO₃, dried over MgSO₄, and filtered. After

concentration in vacuo, FCC provided alcohol 13 (550 mg, 1.60

P r ep a r a tion of Bis(Silyl Eth er ) 15. To a solution of

hemiacetal 12 (2.78 g; 8.03 mmol) in N,N-dimethylformamide

(8.0 mL; 1.0 M) were added imidazole (1.91 g; 28.6 mmol; 3.5

equiv) and tert-butyldimethylsilyl chloride (3.02 g; 20.0 mmol;

2.5 equiv). The resulting solution was stirred at ambient

temperature for 16 h. Dilution with water (8 mL) was followed

by extraction with Et₂O. The combined organic layers were

washed with water and brine, dried over MgSO₄, filtered, and

concentrated in vacuo. FCC (3:1 hexanes-Et₂O) provided the

bis(silyl ether) 15 (4.29 g; 7.47 mmol; 93%). Data for 15: ¹H

NMR (300 MHz, CDCl₃) δ 0.07 (s, 3 H), 0.09 (s, 3 H), 0.14 (s,

3 H), 0.16 (s, 3 H), 0.80-0.95 (m, 30 H), 1.50-1.75 (m, 8 H),

3.53-3.64 (m, 1 H), 3.83-3.91 (m, 1 H), 3.94-4.07 (m, 2 H),

4.47 (d, J ) 7.8 Hz, 1 H), 4.77 (dd, J ) 7.8, 4.0 Hz, 1 H), 5.20

(s, 1 H).

P r ep a r a tion of Hem ia ceta l 16. A solution of tetra-n-

butylammonium fluoride (1.0 M in THF; 7.55 mL; 7.55 mmol;

1.1 equiv) was added dropwise to a solution of the bis(silyl

ether) 15 (3.94 g; 6.87 mmol) in THF (34 mL; 0.20 M) at 0 °C.

After 10 min of stirring at this temperature, the reaction

mixture was filtered through a plug of silica gel, rinsed with

ether, and concentrated in vacuo. FCC (3:1 hexanes-Et₂O) of

the crude residue provided hemiacetal 16 (3.00 g; 6.53 mmol;

95%). Data for 16: ¹H NMR (300 MHz, CDCl₃) δ 0.14 (s, 3 H),

0.16 (s, 3 H), 0.83-0.97 (m, 21 H), 1.52-1.74 (m, 8 H), 3.53-

3.62 (m, 1 H), 3.96-4.09 (m, 3 H + OH), 4.54 (d, J ) 7.8 Hz,

1 H), 4.77 (dd, J ) 7.8, 3.6 Hz, 1 H), 5.30 (s, 1 H).

mmol, 65%). Data for 13: R_f0.31 (1:2 hexanes-Et₂O); [R]²⁴

D

-46.1° (c 1.10, CHCl₃); IR (thin film) 3500 (br), 1785 cm^-1; ¹H

NMR (300 MHz, CDCl₃) δ 0.83-0.93 (m, 12 H), 1.57-1.72 (m,

8 H), 2.64 (d, J ) 7.7 Hz, OH), 3.86-3.93 (m, 2 H), 4.08 (m, 1

H), 4.31 (td, J ) 7.1, 2.8 Hz, 1 H), 4.40 (dd, J ) 9.1, 3.6 Hz, 1

H), 4.82 (d, J ) 5.4 Hz, 1 H), 4.95 (dd, J ) 5.4, 3.6 Hz, 1 H);

¹³C NMR (75 MHz, CDCl₃) δ 7.44 (CH₃), 7.90 (CH₃), 8.01 (CH₃),

8.06 (CH₃), 28.53 (CH₂), 29.16 (CH₂), 29.38 (CH₂), 29.77 (CH₂),

65.72 (CH₂), 67.94 (CH), 75.30 (CH), 75.99 (CH), 76.35 (CH),

77.91 (CH), 113.19 (C), 118.12 (C), 173.27 (C); HRMS calcd

for C₁₅H₂₃O₇(M⁺- C₂H₅) 315.1444, found 315.1465.

P r ep a r a t ion of Hem ia cet a l 12. Crushed cerium(III)

chloride heptahydrate (8.06 g; 21.7 mmol; 1.5 equiv) was added

in portions to ketolactone 11 (4.96 g; 14.5 mmol) in MeOH (150

mL; 0.0967 M) at room temperature. The temperature was

lowered to -78 °C, causing the reaction mixture to become

quite viscous. Finely crushed sodium borohydride (1.10 g; 29.0

mmol; 2 equiv) was added in one portion, and stirring was

continued for 2 h at -78 °C, 15 min at 0 °C and a few minutes

at room temperature. The solution was reduced to a minimal

volume by removal of solvent in vacuo, and it was further

diluted with Et₂O (30 mL), which precipitated cerium salts.

The salts were dissolved in 0.6 N HCl (20 mL), and upon

partitioning, the aqueous layer was exhaustively extracted

with Et₂O. The combined ethereal extracts were washed with

saturated NaHCO₃, dried over MgSO₄, filtered, and concen-

trated in vacuo. FCC (9:1 to 4:1 PhH-Et₂O) gave an insepa-

rable mixture of the desired hemiacetal 12 and the over-

reduced triol (5 g total; ∼3.5 g hemiacetal; 10.1 mmol, ∼70%).

This mixture was taken directly into the following oxidation.

P r ep a r a tion of Alcoh ol 13 fr om 12. To the hemiacetal/

triol mixture above (3.5 g/1.5 g; 10 mmol/4 mmol) in CH₂Cl₂

(100 mL; 0.17 M) at room temperature was added crushed 4

Å molecular sieves (30 g) that had been allowed to cool after

being placed in a 350 °C oven for at least a week. Pyridinium

dichromate (9.6 g; 25 mmol; 1.5 equiv) was added in portions,

and the mixture was stirred vigorously for 2 h, at which point

the overoxidized ketone 11 was observed on TLC. Celite was

added until stirring became difficult, and dry Et₂O (300 mL)

was added slowly, creating a fine brown powder that could be

easily filtered from the reaction mixture through silica gel.

Concentration of the filtrate in vacuo followed by FCC of the

crude residue (9:1 PhH-Et₂O) gave the desired alcohol 13 (3.4

g; 9.8 mmol; 58%). See data for 13 above.

P r ep a r a tion of Silyl Eth er 14. To a solution of alcohol

13 (2.00 g; 5.81 mmol) in N,N-dimethylformamide (5.8 mL;

1.0 M) were added imidazole (3.95 g; 58.1 mmol; 10 equiv) and

tert-butyldimethylsilyl chloride (4.38 g; 29.1 mmol; 5.0 equiv).

The resulting solution was stirred at ambient temperature for

16 h. Dilution with water (10 mL) was followed by extraction

with Et₂O. The combined organic layers were washed with

water and brine, dried over MgSO₄, filtered, and concentrated

in vacuo. Recrystallization of the crude solid from hexanes gave

2.3 g (5.1 mmol; 88%) of 14 as colorless crystals. Data for 14:

R_f0.62 (1:2 hexanes-Et₂O); mp 91-92 °C; [R]²⁴_D-20.3° (c 1.16,

CHCl₃); IR (thin film) 1794 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ 0.13 (s, 3 H), 0.16 (s, 3 H), 0.83-0.93 (m, 21 H), 1.58-1.73

(m, 8 H), 3.59-3.67 (m, 1 H), 3.99-4.14 (m, 3 H), 4.26 (dd, J

) 9.1, 3.3 Hz, 1 H), 4.78 (d, J ) 5.3 Hz, 1 H), 4.87 (dd, J ) 5.3,

3.3 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ -5.15 (CH₃), -4.15

(CH₃), 7.69 (CH₃), 8.07 (CH₃), 8.47 (CH₃), 18.43 (C), 26.00

P r ep a r a tion of La cton e 14 fr om 16. To a solution of

hemiacetal 16 (4.40 g; 9.57 mmol) in CH₂Cl₂(80 mL; 0.12 M)

were added crushed 4 Å molecular sieves (17.5 g) and pyri-

dinium dichromate (5.39 g; 14.3 mmol; 1.5 equiv) in portions.

After the mixture was stirred at room temperature for 2 h,

Celite was added followed by filtration of the reaction mixture

through silica gel. Purification by FCC (3:1 hexanes-Et₂O)

provided 2.98 g of lactone 14 (6.51 mmol; 68%). See data for

14 above.

P r ep a r a tion of P yr a n on e 19. A solution of n-butyllithium

(0.81 mL of a 2.33 M solution in hexanes; 1.9 mmol) was added

dropwise to a solution of (trimethylsilyl)diazomethane (0.98

mL of a 2.0 M solution in hexane; 2.0 mmol) in dry Et₂O (5

mL) at -5 °C. This solution was stirred at -5 to 0 °C for 20

min before being added to a solution of lactone 14 (570 mg;

1.25 mmol) in Et₂O (10 mL; 0.12 M) at -78 °C. The resulting

yellow solution was stirred at -78 °C for 3 h followed by

quenching with 0.6 N HCl (10 mL). After being warmed to 0

°C, the mixture was poured into 0.6 N HCl (10 mL) and

extracted with Et₂O. The combined ether layers were washed

with saturated NaHCO₃, dried over MgSO₄, filtered, and

concentrated in vacuo. The resulting residue was dissolved in

dry benzene (5 mL) and 4 Å MS (ca. 15 beads) were added.

After being stirred at room temperature for 1 h, the solution

was added to rhodium(II) acetate dimer (11 mg; 0.025 mmol)

in refluxing benzene (80 mL). The mixture was heated at reflux

for 40 min, cooled to room temperature, and concentrated in

vacuo. Purification of the crude residue by FCC (2:1 hexanes-

Et₂O) provided 443 mg of pyranone 19 (0.939 mmol; 75%). Data

for 19: ¹H NMR (270 MHz, CDCl₃) δ 0.13 (s, 3 H), 0.16 (s, 3

H), 0.79-0.97 (m, 21 H), 1.51-1.81 (m, 8 H), 3.39 (d, J ) 12.2

Hz, 1 H), 3.60 (at, J ) 13.0 Hz, 1 H), 3.84-4.09 (m, 4 H), 4.27-

4.44 (m, 2 H), 4.75 (dd, J ) 9.8, 2.2 Hz, 1 H).

P r ep a r a tion of Diols 22a a n d 22b fr om r a c-21. R-Alk-

oxystannane rac-21 (13.5 g; 30.0 mmol; 1.7 equiv) was dis-

solved in THF (60 mL; 0.50 M) and cooled to -78 °C for the

dropwise addition of a 1.14 M solution of n-BuLi in hexanes

(26 mL; 30 mmol; 1.7 equiv) over 30 min. Stirring was

continued for 10 min, and a solution of 14 (8.0 g; 17 mmol) in

THF (116 mL; 0.15 M) was added dropwise to the organo-

lithium species over 30 min. Stirring was continued for

approximately 1 h, and the reaction mixture was quenched

with 1.8 N HCl (350 mL) followed by slow warming to room

temperature. The turbid mixture was extracted thoroughly

4082 J . Org. Chem., Vol. 65, No. 13, 2000

Burke et al.

with Et₂O, and the ethereal layers were concentrated and

redissolved in THF (60 mL) and 1.8 N HCl (60 mL) and stirred

at room temperature for 2 h. (This second hydrolysis was

necessary to completely remove the ethoxyethyl protecting

group.) Extraction with Et₂O was followed by washes of the

combined extracts with water, saturated NaHCO₃, and brine.

The organic extracts were then dried over MgSO₄, filtered,

concentrated in vacuo, and subjected to FCC (3:1 to 1:1

hexanes-Et₂O) to afford 3.3 g of the desired diastereomer 22a

(6.1 mmol; 35%) and 3.8 g of the undesired diastereomer 22b

(7.0 mmol; 40%). Data for 22a : R_f0.21 (1:1 hexanes-Et₂O);

the addition of MsCl (21 µL; 0.28 mmol; 1.1 equiv). Stirring

was continued for 45 min, keeping the temperature between

-40 and -50 °C, at which point the reaction mixture was

quenched with water (5 mL) and allowed to warm to room

temperature. The layers were partitioned, and the aqueous

layer was extracted with CH₂Cl₂followed by washes of the

combined organic layers with 0.6 N HCl, water, and saturated

NaHCO₃. The organic layers were then dried over MgSO₄,

filtered, concentrated in vacuo and subjected to FCC (3:1 to

1:1 to 1:2 hexanes-Et₂O) to give 127 mg of mesylate 23 (0.204

mmol; 82%) as a colorless oil. Data for 23: R_f0.36 (1:2

[R]²⁴_D+6.5° (c 1.04, CHCl₃); IR (thin film) 3450 (br), 1680 cm^-1

;

hexanes-Et₂O); [R]²⁴-3.3° (c 2.40, CHCl₃); IR (thin film)

D

¹H NMR (300 MHz, CDCl₃) δ 0.12 (s, 3 H), 0.14 (s, 3 H), 0.80-

0.98 (m, 21 H), 1.52-1.79 (m, 10 H and OH), 2.15 (m, 1 H),

2.27-2.43 (m, 2 H), 2.72 (m, OH), 3.46-3.56 (m, 1 H), 3.80-

4.04 (m, 4 H), 4.52 (d, J ) 5.9 Hz, 1 H), 4.82 (dd, J ) 5.9, 3.0

Hz, 1 H), 4.96-5.09 (m, 2 H), 5.74-5.89 (m, 1 H); ¹³C NMR

(75 MHz, CDCl₃) δ -5.28 (CH₃), -4.09 (CH₃), 7.86 (CH₃), 7.99

(CH₃), 8.13 (CH₃), 8.44 (CH₃), 18.43 (C), 26.07 (CH₃), 28.78

(CH₂), 28.90 (CH₂), 29.62 (CH₂), 29.75 (CH₂), 29.97 (CH₂), 67.24

(CH₂), 70.89 (CH), 71.50 (CH), 79.77 (CH), 80.03 (CH), 80.89

(CH), 85.05 (CH), 106.30 (C), 111.87 (C), 115.02 (CH₂), 116.80

(C), 138.13 (CH); HRMS calcd for C₂₆H₄₇O₈Si (M⁺- C₂H₅)

515.3040, found 515.3053. Data for 22b: R_f0.47 (1:1 hexanes-

3200-3600 (br), 1641 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 0.12

(s, 3 H), 0.14 (s, 3 H), 0.83-0.97 (m, 21 H), 1.53-1.90 (m, 10

H), 2.15-2.40 (m, 2 H), 2.85 (s, OH), 3.14 (s, 3 H), 3.48-3.53

(m, 1 H), 3.95-4.07 (m, 4 H), 4.48 (d, J ) 5.9 Hz, 1 H), 4.86

(dd, J ) 6.0, 2.2 Hz, 1 H), 4.95 (at, J ) 6.4, 1 H), 4.99-5.12

(m, 2 H), 5.74-5.89 (m, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ

-5.22 (CH₃), -4.14 (CH₃), 7.86 (CH₃), 8.00 (CH₃), 8.09 (CH₃),

8.47 (CH₃), 18.45 (C), 26.06 (CH₃), 28.61 (CH₂), 28.77 (CH₂),

28.82 (CH₂), 29.14 (CH₂), 29.57 (CH₂), 29.96 (CH₂), 38.73 (CH₃),

66.99 (CH₂), 71.13 (CH), 79.56 (CH), 80.09 (CH), 80.71 (CH),

81.24 (CH), 84.27 (CH), 104.86 (C), 112.06 (C), 115.52 (CH₂),

117.29 (C), 137.16 (CH); HRMS calcd for C₂₆H₄₅O₇Si (M⁺

-

Et₂O); [R]²⁴-9.7° (c 1.16, CHCl₃); IR (thin film) 3200-3600

C₂H₅- CH₃SO₃H) 497.2934, found 497.2890.

D

1

(br), 1641 cm^-1; H NMR (300 MHz, CDCl₃) δ 0.12 (s, 3 H),

P r ep a r a tion of P yr a n on e 6. A solution of hydroxy mes-

ylate 23 (150 mg; 0.241 mmol) in benzene (24 mL; 0.01 M)

was cooled to 5 °C for the dropwise addition of a 3.0 M solution

of EtMgBr in Et₂O (0.080 mL; 0.24 mmol; 1.0 equiv). The

solution was stirred at 5 °C for 1 h and was warmed to room

temperature where it was stirred for 10 min before being

heated to a vigorous reflux for 25 min. The reaction mixture

was then cooled to room temperature and poured into 10 mL

of 0.6 N HCl. The aqueous phase was extracted with Et₂O,

and the combined organic layers were washed with water

followed by saturated NaHCO₃and dried over Na₂SO₄. Filtra-

tion and concentration in vacuo gave a crude oil that was

purified by FCC (20:1 benzene-Et₂O followed by 1:1 to 1:2

hexanes-Et₂O) to yield 63 mg of pyranone 6 (0.12 mmol; 50%)

and 38 mg of ketone 25 (0.072 mmol; 30%). Data for 6: R_f

0.45 (3:1 hexanes-Et₂O); [R]²⁴_D-24.1° (c 1.15, CHCl₃); IR (thin

film) 1738, 1655 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 0.14 (s, 3

H), 0.15 (s, 3 H), 0.87-0.96 (m, 21 H), 1.56-1.95 (m, 10 H),

2.07-2.32 (m, 2 H), 3.53 (m, 1 H), 3.69 (t, J ) 8.4 Hz, 1 H),

3.93 (dd, J ) 8.4, 6.4 Hz, 1 H), 4.00 (dd, J ) 8.4, 6.4 Hz, 1 H),

4.13 (dt, J ) 8.4, 6.4 Hz, 1 H), 4.34 (d, J ) 7.4 Hz, 1 H), 4.36

(dd, J ) 9.4, 4.0 Hz, 1 H), 4.70 (dd, J ) 7.4, 1.3 Hz, 1 H), 4.99-

5.07 (m, 2 H), 5.73-5.81 (m, 1 H); ¹³C NMR (75 MHz, CDCl₃)

δ -4.71 (CH₃), -3.98 (CH₃), 8.00 (CH₃), 8.27 (CH₃), 8.35 (CH₃),

8.51 (CH₃), 18.55 (C), 26.20 (CH₂), 27.85 (CH₂), 28.92 (CH₂),

28.97 (CH₂), 29.07 (CH₂), 29.61 (CH₂), 29.65 (CH₂), 66.78 (CH₂),

71.93 (CH), 73.22 (CH), 76.06 (CH), 76.50 (CH), 77.94 (CH),

79.23 (CH), 112.03 (C), 115.81 (CH₂), 116.38 (C), 136.91 (CH),

207.42 (C); HRMS calcd for C₂₆H₄₅O₇Si (M⁺- C₂H₅) 497.2934,

found 497.2930. Data for 25: R_f0.43 (3:1 hexanes:Et₂O); IR

0.13 (s, 3 H), 0.75-0.97 (m, 21 H), 1.49-1.81 (m, 10 H), 2.16

(m, 1 H), 2.22-2.41 (m, 1 H and OH), 3.61 (t, J ) 8.3 Hz, 1

H), 3.83 (m, 1 H), 3.90 (s, OH), 3.92-4.00 (m, 3 H), 4.10 (m, 1

H), 4.44 (d, J ) 5.9 Hz, 1 H), 4.81 (dd, J ) 5.9, 3.0 Hz, 1 H),

4.94-5.10 (m, 2 H), 5.76-5.90 (m, 1 H); ¹³C NMR (75 MHz,

CDCl₃) δ -5.13 (CH₃), -4.24 (CH₃), 7.92 (CH₃), 8.09 (CH₃),

8.18 (CH₃), 8.44 (CH₃), 18.47 (C), 26.05 (CH₃), 28.69 (CH₂),

28.82 (CH₂), 29.56 (CH₂), 29.59 (CH₂), 29.62 (CH₂), 29.70 (CH₂),

66.65 (CH₂), 71.22 (CH), 72.41 (CH), 79.37 (CH), 79.57 (CH),

80.69 (CH), 84.09 (CH), 106.15 (C), 112.25 (C), 114.60 (CH₂),

116.35 (C), 138.38 (CH); HRMS calcd for C₂₆H₄₇O₈Si (M⁺

C₂H₅) 515.3040, found 515.3015.

-

Recyclin g of 22b. Solid periodic acid (478 mg; 2.10 mmol;

1.2 equiv) was added at room temperature to a solution of 22b

(956 mg; 1.75 mmol) in THF (35 mL; 0.050 M). After 30 min,

dry Et₂O (9 mL) and Na₂SO₄(525 mg) were added, and stirring

was continued at room temperature for another 20 min. Slow

filtration of the reaction mixture through a frit funnel half full

of Et₂O-saturated silica gel ensured complete separation of the

solid byproduct from the desired product. The crude product

was recrystallized from hexanes to give 730 mg of lactone 14

(1.59 mmol; 91%). See data for 14 above.

P r ep a r a tion of Diol 22a fr om 6(S)-21. R-Alkoxystannane

6(S)-21 (180 mg; 0.402 mmol; 2.0 equiv) was dissolved in THF

(0.5 mL; 0.8 M) and cooled to -78 °C for the dropwise addition

of a 2.5 M solution of n-BuLi in hexanes (0.16 mL; 0.40 mmol;

2.0 equiv) over 30 min. Stirring was continued for 10 min, and

a solution of 14 (90 mg; 0.20 mmol; 1.0 equiv) in THF (1.0

mL; 1.0 M) was added dropwise to the organolithium species

over 30 min. Stirring was continued for approximately 2.5 h,

and the reaction mixture was quenched with 1.8 N HCl (4 mL)

followed by slow warming to room temperature with continued

stirring for 15 min. The turbid mixture was extracted thor-

oughly with Et₂O, and the ether layers were concentrated and

redissolved in THF (5 mL) and 1.8 N HCl (5 mL) and stirred

at room temperature for 2 h. (This second hydrolysis was

necessary to completely remove the ethoxyethyl protecting

group.) Extraction with Et₂O was followed by washes of the

combined extracts with water, saturated NaHCO₃and brine.

The organic extracts were then dried over MgSO₄, filtered,

concentrated in vacuo, and subjected to FCC (3:1 to 1:1

hexanes-Et₂O) to give 75 mg of 22a (0.14 mmol; 70%) and 5

mg of 22b (0.009 mmol; 5%) as colorless oils. See data for 22a

and 22b above.

1

(neat) 1718, 1641 cm^-1; H NMR (300 MHz, CDCl₃) δ 0.13 (s,

3 H), 0.14 (s, 3 H), 0.85-0.95 (m, 21 H), 1.50-1.75 (m, 8 H),

2.31 (m, 2 H), 2.64 (m, 2 H), 3.49 (dd, J ) 8.0, 3.4 Hz, 1 H),

3.68 (t, J ) 8.2 Hz, 1 H), 3.95-4.16 (m, 3 H), 4.33 (br s, 1 H),

4.68 (dd, J ) 6.4, 3.4 Hz, 1 H), 4.95-5.12 (m, 3 H), 5.70-5.85

(m, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ -5.08 (CH₃), -4.22

(CH₃), 7.67 (CH₃), 8.10 (CH₃), 8.20 (CH₃), 8.30 (CH₃), 18.47

(C), 26.08 (CH₂), 27.16 (CH₂), 29.16 (CH₂), 29.47 (CH₂), 29.55

(CH₂), 29.95 (CH₂), 38.07 (CH₂), 66.84 (CH₂), 71.19 (CH), 79.38

(CH), 80.64 (CH), 81.80 (CH), 83.39 (CH), 88.89 (CH), 112.01

(C), 115.60 (CH₂), 117.00 (C), 136.68 (CH), 209.05 (C); MS

(FAB) m/e (relative intensity, assignment) 549.2 (83, M + Na⁺),

497.2 (25, M⁺- C₂H₅).

P r ep a r a tion of Hyd r oxy Mesyla te 26. Diol 22b (75 mg;

0.14 mmol) and a catalytic amount of DMAP (0.5 mg; 0.004

mmol; 0.03 equiv) were dissolved in CH₂Cl₂(1.5 mL; 0.09 M)

at room temperature. The solution was cooled to -15 °C for

the successive addition of triethylamine (81 µL; 0.58 mmol;

4.1 equiv) and methanesulfonyl chloride (20 µL; 0.26 mmol;

1.9 equiv). Stirring was continued for 10 min, keeping the

P r ep a r a tion of Hyd r oxy Mesyla te 23. Diol 22a (136 mg;

0.250 mmol) and a catalytic amount of DMAP (2.0 mg; 0.013

mmol; 0.05 equiv) were dissolved in CH₂Cl₂(2.5 mL; 0.10 M)

at room temperature. Triethylamine (42 µL; 0.30 mmol; 1.2

equiv) was added, and the solution was cooled to -50 °C for

Halichondrin B: Synthesis of the C(1)-C(15) Subunit

J . Org. Chem., Vol. 65, No. 13, 2000 4083

temperature between -15 and -10 °C, at which point the

reaction mixture was quenched with water (1 mL) and allowed

to warm to room temperature. The layers were partitioned,

and the aqueous layer was extracted with Et₂O followed by

washes of the combined organic layers with 0.6 N HCl, water,

and saturated NaHCO₃. The combined organic layers were

dried over MgSO₄, filtered, concentrated in vacuo, and sub-

jected to FCC (1:1 hexanes-Et₂O) to provide 64 mg of hydroxy

mesylate 26 (0.10 mmol; 73%) as a colorless oil. Data for 26:

¹H NMR (270 MHz, CDCl₃) δ 0.13 (as, 6 H), 0.75-1.00 (m, 21

H), 1.48-1.77 (m, 6 H), 1.87-2.04 (m, 2 H), 2.11-2.40 (m, 2

H), 2.63 (s, OH), 3.09 (s, 3 H), 3.63-3.78 (m, 1 H), 3.96-4.16

(m, 4 H), 4.47 (d, J ) 8.1 Hz, 1 H), 4.84 (dd, J ) 8.1, 3.9 Hz,

1 H), 4.91 (dd, J ) 11.7, 5.6 Hz, 1 H), 4.98-5.21 (m, 2 H),

5.71-5.94 (m, 1 H).

P r ep a r a tion of P yr a n on e 27. A solution of hydroxy

mesylate 26 (62 mg; 0.10 mmol) in benzene (5.0 mL; 0.020 M)

was cooled to 5 °C for the dropwise addition of a 0.3 M solution

of EtMgBr in PhH-Et₂O (0.33 mL; 0.10 mmol; 1.0 equiv). The

solution was stirred at 5 °C for 10 min and was warmed to

room temperature where it was stirred for 10 min before being

heated to a vigorous reflux for 25 min. The reaction mixture

was then cooled to room temperature and poured into 10 mL

of 0.6 N HCl. The aqueous phase was extracted with Et₂O,

and the combined organic layers were washed with water

followed by saturated NaHCO₃and dried over MgSO₄. Filtra-

tion and concentration in vacuo gave a crude oil that was

purified by FCC (3:1 hexanes-Et₂O) to yield 43 mg of pyranone

27 (0.082 mmol; 82%). Data for 27: ¹H NMR (270 MHz, CDCl₃)

δ 0.14 (s, 3 H), 0.19 (s, 3 H), 0.73-1.04 (m, 21 H), 1.51-1.96

(m, 10 H), 2.02-2.35 (m, 2 H), 3.40 (d, J ) 11.9 Hz, 1 H), 3.66

(at, J ) 11.4 Hz, 1 H), 3.83 (dd, J ) 11.1, 7.2 Hz, 1 H), 3.89-

4.15 (m, 3 H), 4.33 (d, J ) 10.0 Hz, 1 H), 4.74 (dd, J ) 10.0,

2.5 Hz, 1 H), 4.94-5.13 (m, 2 H), 5.67-5.91 (m, 1 H).

triturated with hexanes to remove excess ylide and Ph₃P(O).

The hexanes solution was concentrated in vacuo, and the

remaining residue was purified by FCC (8:1 to 1:1 hexanes-

Et₂O) to give 150 mg (0.256 mmol; 88%) of enoate 29. Data

for 29: R_f0.26 (1:1 hexanes-Et₂O); [R]²⁴-34.9° (c 2.03,

D

CHCl₃); IR (thin film) 3450 (br), 1725 cm^-1; ¹H NMR (300 MHz,

CDCl₃) δ 0.11 (s, 3 H), 0.12 (s, 3 H), 0.86-0.95 (m, 21 H), 1.56-

1.90 (m, 10 H), 2.06 (d, J ) 10.4 Hz, OH), 2.20-2.47 (m, 2 H),

3.37 (dd, J ) 8.7, 1.0 Hz, 1 H), 3.51 (td, J ) 10.1, 2.7 Hz, 1 H),

3.62-3.72 (m, 2 H), 3.72 (s, 3 H), 3.77 (dd, J ) 8.4, 6.4 Hz, 1

H), 3.94 (dd, J ) 8.4, 6.4 Hz, 1 H), 4.03 (dt, J ) 9.1, 6.4 Hz, 1

H), 4.45-4.51 (m, 2 H), 5.82-5.85 (m, 1 H), 6.97 (dt, J ) 15.8,

6.7 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ -4.73 (CH₃), -4.07

(CH₃), 8.01 (CH₃), 8.19 (CH₃), 8.28 (CH₃), 8.62 (CH₃), 18.51

(C), 26.19 (CH₃), 28.08 (CH₂), 28.26 (CH₂), 28.66 (CH₂), 29.25

(CH₂), 29.75 (CH₂), 31.07 (CH₂), 51.39 (CH₃), 66.97 (CH₂), 68.84

(CH), 71.44 (CH), 72.11 (CH), 72.60 (CH), 73.08 (CH), 73.60

(CH), 78.81 (CH), 111.64 (C), 113.94 (C), 121.12 (CH), 148.78

(CH), 166.95 (C); HRMS calcd for C₂₈H₄₉O₉Si (M⁺- C₂H₅)

557.3146, found 557.3159.

P r ep a r a tion of Ester 30. A 40% solution of benzyltri-

methylammonium methoxide in MeOH (0.75 mL; 1.5 mmol; 3

equiv) was added dropwise to a solution of 29 (294 mg; 0.502

mmol) in benzene (50 mL; 0.010 M) that had been cooled to 5

°C. The reaction mixture was stirred at 5 °C for 10 min and

was then warmed to 18 °C where it was stirred for 3 h.

Although 29 is consumed within 10 min at 18 °C, the

additional stirring time is necessary to ensure complete

equilibration of the initially formed C(3) axial isomer to the

desired C(3) equatorial isomer. Quenching with 0.6 N HCl (20

mL) was followed by extraction of the aqueous layer with Et₂O.

The combined organic layers were washed again with 0.6 N

HCl and brine, dried over MgSO₄, filtered, and concentrated

in vacuo. FCC (3:1 hexanes-Et₂O) of the crude residue

provided 260 mg (0.444 mmol; 88%) of ester 30 as a colorless

P r ep a r a tion of Alcoh ol 28. A solution of pyranone 6 (450

mg; 0.856 mmol) in THF (28 mL; 0.03 M) was cooled to -78

°C for the dropwise addition of a 1.0 M solution of DIBALH in

PhCH₃(5.1 mL; 5.1 mmol; 6 equiv). The reaction mixture was

stirred for 3 h and was transferred into a freshly prepared

saturated solution of potassium sodium tartrate (50 mL). The

cloudy solution was allowed to warm to room temperature and

stir for 30 min during which time it became clear indicating

that all the aluminum salts had dissolved. Extraction with

Et₂O was followed by a brine wash of the combined ether

layers, which were then dried over MgSO₄, filtered, and

concentrated in vacuo. FCC (8:1 to 2:1 hexanes-Et₂O) resulted

in a 99% yield of the desired alcohol 28 (447 mg; 0.847 mmol).

Data for 28: R_f0.52 (1:1 hexanes-Et₂O); [R]²⁴_D-25.4° (c 0.820,

oil. Data for 30: R_f0.39 (1:1 hexanes-Et₂O); [R]²⁴-2.7° (c

D

2.64, CHCl₃); IR (thin film) 1743 cm^-1

;

¹H NMR (300 MHz,

CDCl₃) δ 0.11 (s, 3 H), 0.13 (s, 3 H), 0.86-1.00 (m, 21 H), 1.40-

1.85 (m, 11 H), 1.96 (m, 1 H), 2.42 (ABX, J _AB) 16.2 Hz, J _AX

)

5.9 Hz, 1 H), 2.71 (ABX, J _AB) 16.2 Hz, J _BX) 6.9 Hz, 1 H),

3.44-3.61 (m, 3 H), 3.66 (s, 3 H), 3.74-3.99 (m, 5 H), 4.51 (m,

2 H); ¹³C NMR (75 MHz, CDCl₃) δ -5.01 (CH₃), -4.09 (CH₃),

7.64 (CH₃), 7.99 (CH₃), 8.06 (CH₃), 8.56 (CH₃), 18.37 (C), 26.10

(CH₃), 28.10 (CH₂), 28.52 (CH₂), 29.60 (CH₂), 29.94 (CH₂), 30.08

(CH₂), 30.26 (CH₂), 40.09 (CH₂), 51.46 (CH₃), 66.44 (CH), 67.52

(CH₂), 71.75 (CH), 71.92 (CH), 72.83 (CH), 73.85 (CH), 75.50

(CH), 76.62 (CH), 80.02 (CH), 111.11 (C), 113.89 (C), 171.29

(C); HRMS calcd for C₂₈H₄₉O₉Si (M⁺- C₂H₅) 557.3146, found

557.3147.

CHCl₃); IR (thin film) 3200-3600 (br) cm^-^{1 1}H NMR (300

;

MHz, CDCl₃) δ 0.12 (s, 3 H), 0.13 (s, 3 H), 0.87-0.96 (m, 21

H), 1.53-1.79 (m, 10 H), 1.96 (d, J ) 10.7 Hz, OH), 2.05-2.35

(m, 2 H), 3.35 (dd, J ) 8.7, 0.7 Hz, 1 H), 3.52 (td, J ) 10.1, 2.7

Hz, 1 H), 3.58-3.71 (m, 2 H), 3.78 (m, 1 H), 3.95-4.05 (m, 2

H), 4.47-4.52 (m, 2 H), 4.94-5.05 (m, 2 H), 5.77-5.84 (m, 1

H); ¹³C NMR (75 MHz, CDCl₃) δ -4.76 (CH₃), -4.05 (CH₃),

8.01 (CH₃), 8.17 (CH₃), 8.27 (CH₃), 8.60 (CH₃), 18.52 (C), 26.21

(CH₃), 28.20 (CH₂), 28.71 (CH₂), 29.30 (CH₂), 29.72 (CH₂), 29.81

(CH₂), 31.94 (CH₂), 67.18 (CH₂), 68.89 (CH), 71.50 (CH), 72.36

(CH), 72.87 (CH), 73.23 (CH), 73.83 (CH), 79.07 (CH), 111.53

(C), 113.87 (CH₂), 114.71 (C), 138.12 (CH); HRMS calcd for

P r ep a r a tion of Silyl Eth er 32. To a solution of alcohol 8

(7.17 g; 20.9 mmol) in N,N-dimethylformamide (21 mL; 1.0

M) were added imidazole (2.14 g; 31.4 mmol; 1.5 equiv) and

tert-butyldimethylsilyl chloride (4.41 g; 29.3 mmol; 1.4 equiv).

The resulting solution was stirred at room temperature for

16 h. Dilution with water (30 mL) was followed by extraction

with Et₂O. The combined organic layers were washed with

water and brine, dried over MgSO₄, filtered, and concentrated

in vacuo. FCC (3:1 hexanes-Et₂O) of the crude product

afforded 8.52 g (18.6 mmol; 89%) of the silyl ether 32 as a clear

colorless oil which solidified upon drying under vacuum. Data

C

₂₆H₄₇O₇Si (M⁺- C₂H₅) 499.3091, found 499.3067.

for 32: R_f0.34 (1:1 hexanes-Et₂O); mp 72-73.5 °C;[R]²³

D

P r ep a r a tion of En oa te 29. The alcohol 28 (154 mg; 0.292

-24.0° (c 1.14, CHCl₃); IR (thin film) 1776 cm^-1; ¹H NMR (300

MHz, CDCl₃) δ 0.09 (s, 3 H), 0.16 (s, 3 H), 0.86-0.95 (m, 21

H), 1.58-1.75 (m, 8 H), 3.80-3.92 (m, 1 H), 4.04-4.24 (m, 3

H), 4.28 (dd, J ) 9.0, 2.9 Hz, 1 H), 4.80 (d, J ) 5.2 Hz, 1 H),

4.86 (dd, J ) 5.2, 2.9 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ

-4.67 (CH₃), -4.21 (CH₃), 7.53 (CH₃), 8.04 (CH₃), 8.10 (CH₃),

18.16 (C), 25.80 (CH₃), 28.75 (CH₂), 29.47 (CH₂), 29.52 (CH₂),

29.75 (CH₂), 67.90 (CH₂), 71.32 (CH), 76.53 (CH), 76.62 (CH),

77.19 (CH), 81.01 (CH), 113.69 (C), 117.63 (C), 173.23 (C);

mmol) was added to a two-neck flask equipped with a gas inlet

tube and a drying tube with the aid of CH₂Cl₂(10 mL; 0.029

M). Nitrogen was bubbled through the solution for 10 min,

and the solution was then cooled to -78 °C. Ozone was bubbled

through the solution until a blue color persisted for 5 min. The

reaction mixture was then purged with nitrogen until the blue

color dissipated, and Ph₃P (153 mg; 0.584 mmol; 2 equiv) was

added to quench. Stirring was continued at -78 °C for 5 min,

and the solution was then allowed to warm to room temper-

ature where it stirred for 1 h. Methyl(triphenylphosphor-

anylidene)acetate (968 mg; 2.90 mmol; 10 equiv) was added,

and stirring was continued for 5 h at room temperature. The

solvent was removed in vacuo, and the crude residue was

HRMS calcd for

481.2610.

C

₂₃H₄₂O₇Si (M + Na⁺) 481.2598, found

P r ep a r a tion of Diols 33a a n d 33b. R-Alkoxystannane rac-

20 (1.89 g; 4.23 mmol; 1.2 equiv) was dissolved in THF (5.0

mL; 0.85 M) and cooled to -78 °C for the dropwise addition of

4084 J . Org. Chem., Vol. 65, No. 13, 2000

Burke et al.

a 2.35 M solution of n-BuLi in hexanes (1.80 mL; 4.23 mmol;

1.2 equiv) over 30 min. Stirring was continued for 10 min, and

a solution of 32 (1.61 g; 3.53 mmol) in THF (9.7 mL; 0.37 M)

was added dropwise to the organolithium species over 30 min.

Stirring was continued for approximately 1 h, and the reaction

mixture was quenched with 1.8 N HCl (70 mL) followed by

slow warming to room temperature. The turbid mixture was

extracted thoroughly with Et₂O, and the ethereal layers were

concentrated and redissolved in THF (12 mL) and 1.8 N HCl

(12 mL) and stirred at room temperature for 2 h. (This second

hydrolysis was necessary to completely remove the ethoxyethyl

protecting group.) Extraction with Et₂O was followed by

washes of the combined extracts with water, saturated NaH-

CO₃, and brine. The extracts were then dried over MgSO₄,

filtered, concentrated in vacuo and subjected to FCC (5:1 to

3:1 to 1:1 hexanes-Et₂O) to give 697 mg of the desired

diastereomer 33a (1.28 mmol; 36%) and 911 mg of the

undesired diastereomer 33b (1.67 mmol; 47%). Data for 33a :

IR (thin film) 3475 (br), 1640 cm^-1; ¹H NMR (300 MHz, CDCl₃)

δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.81-1.01 (m, 21 H), 1.49-1.80

(m, 8 H), 1.80-2.08 (m, 2 H), 2.17-2.49 (m, 2 H), 2.44 (s, OH),

3.17 (s, 3 H), 3.86 (dd, J ) 8.3, 7.7 Hz, 1 H), 3.91 (dd, J ) 9.2,

3.5 Hz, 1 H), 3.97 (dd, J ) 7.6, 6.1 Hz, 1 H), 4.14 (ddd, J )

8.7, 6.0, 4.1 Hz, 1 H), 4.28 (dd, J ) 9.1, 4.1 Hz, 1 H), 4.52 (d,

J ) 6.0 Hz, 1 H), 4.76 (dd, J ) 5.9, 3.5 Hz, 1 H), 4.96-5.15

(m, 3 H), 5.75-5.91 (m, 1 H); ¹³C NMR (75 MHz, CHCl₃) δ

-4.19 (CH₃), -4.10 (CH₃), 7.89 (CH₃), 8.19 (CH₃), 8.41 (CH₃),

8.55 (CH₃), 18.21 (C), 25.87 (CH₃), 28.65 (CH₂), 29.31 (CH₂),

29.64 (CH₂), 38.82 (CH₃), 66.00 (CH₂), 70.21 (CH), 76.90 (CH),

80.37 (CH), 81.61 (CH), 82.08 (CH), 84.97 (CH), 104.34 (C),

113.02 (CH₂), 115.49 (C), 117.17 (C), 137.18 (CH); HRMS calcd

for C₂₉H₅₄O₁₀SiS (M⁺+ Na) 645.3105, found 645.3090.

P r ep a r a tion of P yr a n on e 35. A solution of hydroxy

mesylate 34 (252 mg; 0.404 mmol) in benzene (25 mL; 0.016

M) was cooled to 5 °C for the dropwise addition of a 3.0 M

solution of EtMgBr in Et₂O (0.14 mL; 0.40 mmol; 1.0 equiv).

The solution was stirred at 5 °C for 1 h and was warmed to

room temperature where it was stirred for 10 min before being

heated to a vigorous reflux for 25 min. The reaction mixture

was then cooled back down to room temperature and poured

into 20 mL of 0.6 N HCl. The aqueous phase was extracted

with Et₂O, and the combined organic layers were washed with

water followed by saturated NaHCO₃and dried over Na₂SO₄.

Filtration and concentration in vacuo gave a crude oil that was

purified by flash column chromatography (5:1 hexanes-Et₂O)

to yield 94 mg of pyranone 35 (0.18 mmol; 43%) and 74 mg of

ketone 36 (0.14 mmol; 35%). Data for 35: R_f0.31 (3:1

R_f0.10 (1:1 hexanes-Et₂O); [R]²³+3.9° (c 2.28, CHCl₃); IR

D

(thin film) 3449 (br), 1640 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ

0.08 (as, 6 H), 0.81-0.97 (m, 21 H), 1.49-1.85 (m, 10 H), 2.11-

2.45 (m, 2 H + 2 OH), 3.83-3.94 (m, 3 H), 3.97 (dd, J ) 7.3,

6.1 Hz, 1 H), 4.14 (ddd, J ) 8.8, 6.0, 4.0 Hz, 1 H), 4.27 (dd, J

) 9.1, 4.1 Hz, 1 H), 4.57 (d, J ) 6.0 Hz, 1 H), 4.71 (dd, J ) 6.0,

3.3 Hz, 1 H), 4.96-5.11 (m, 2 H), 5.76-5.91 (m, 1 H); ¹³C NMR

(75 MHz, CDCl₃) δ -4.29 (CH₃), -4.10 (CH₃), 7.92 (CH₃), 8.18

(CH₃), 8.41 (CH₃), 8.53 (CH₃), 18.30 (C), 25.91 (CH₃), 28.58

(CH₂), 28.61 (CH₂), 28.72 (CH₂), 28.78 (CH₂), 29.70 (CH₂), 30.02

(CH₂), 66.01 (CH₂), 70.40 (CH), 71.56 (CH), 76.93 (CH), 80.29

(CH), 81.97 (CH), 85.85 (CH), 105.90 (C), 112.93 (CH₂), 115.07

(C), 116.64 (C), 138.17 (CH); HRMS calcd for C₂₈H₅₂O₈Si (M

+ Na⁺) 567.3329, found 567.3330. Data for 33b: R_f0.44 (1:1

hexanes-Et₂O); [R]²³_D-7.4° (c 1.82 CHCl₃); IR (thin film) 3600,

3446 (br), 1641 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 0.10 (as, 6

H), 0.79-0.95 (m, 21 H), 1.47-1.88 (m, 10 H + OH), 2.09-

2.40 (m, 2 H), 3.10 (s, OH), 3.82 (dd, J ) 9.2, 3.5 Hz, 1 H),

3.87 (dd, J ) 8.7, 7.6 Hz, 1 H), 3.92-3.97 (m, 1 H), 3.96 (dd,

J ) 7.5, 6.3 Hz, 1 H), 4.16 (ddd, J ) 8.8, 5.9, 3.9 Hz, 1 H), 4.28

(dd, J ) 9.3, 4.1 Hz, 1 H), 4.48 (d, J ) 5.9 Hz, 1 H), 4.70 (dd,

J ) 5.9, 3.6 Hz, 1 H), 4.95-5.13 (m, 2 H), 5.79-5.94 (m, 1 H);

¹³C NMR δ -4.19 (CH₃), -4.03 (CH₃), 7.87 (CH₃), 8.17 (CH₃),

8.41 (CH₃), 8.50 (CH₃), 18.34 (C), 25.83 (CH₃), 28.60 (CH₂),

28.68 (CH₂), 28.74 (CH₂), 28.84 (CH₂), 29.45 (CH₂), 29.71 (CH₂),

65.86 (CH₂), 70.55 (CH), 72.74 (CH), 76.84 (CH), 80.78 (CH),

81.02 (CH), 84.54 (CH), 105.50 (C), 112.87 (CH₂), 114.67 (C),

116.27 (C), 138.34 (CH); HRMS calcd for C₂₈H₅₂O₈Si (M + Na⁺)

567.3329, found 567.3331.

hexanes-Et₂O); [R]²³-9.89° (c 1.81, CHCl₃); IR (thin film)

D

1

1735, 1641 cm^-1; H NMR (300 MHz, CDCl₃) δ 0.09 (s, 3 H),

0.13 (s, 3 H), 0.85-0.96 (m, 21 H), 1.50-1.84 (m, 10 H), 2.06-

2.36 (m, 2 H), 3.63 (d, J ) 7.2 Hz, 1 H), 3.92 (at, J ) 7.9 Hz,

1 H), 4.03 (dd, J ) 7.9, 6.6 Hz, 1 H), 4.17 (dd, J ) 7.4, 4.1 Hz,

1 H), 4.26 (ddd, J ) 7.4, 6.2, 3.9 Hz, 1 H), 4.32 (m, 2 H), 4.65

(dd, J ) 6.8, 1.3 Hz, 1 H), 4.98-5.10 (m, 2 H), 5.72-5.87 (m,

1 H); ¹³C NMR (75 MHz, CDCl₃) δ -4.59 (CH₃), -3.86 (CH₃),

7.81 (CH₃), 8.34 (CH₃), 18.12 (C), 25.98 (CH₃), 27.95 (CH₂),

28.00 (CH₂), 29.13 (CH₂), 29.22 (CH₂), 29.36 (CH₂), 29.40 (CH₂),

66.16 (CH₂), 71.92 (CH), 72.37 (CH), 75.59 (CH), 75.87 (CH),

76.91 (CH), 79.82 (CH), 112.72 (C), 115.59 (CH₂), 115.68 (C),

136.95 (CH), 207.31 (C); HRMS calcd for C₂₈H₅₀O₇Si (M⁺

+

Na) 549.3224, found 549.3197. Data for 36: R_f0.15 (3:1

hexanes:Et₂O); [R]²³_D-33.7 (c 1.72, CHCl₃); IR (thin film) 1721,

1642 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 0.15 (s, 3 H), 0.18 (s,

3 H), 0.78-0.96 (m, 21 H), 1.46-1.74 (m, 8 H), 2.30-2.40 (m,

2 H), 2.72-2.80 (m, 2 H), 3.27 (dd, J ) 8.8, 3.3 Hz, 1 H), 3.89

(at, J ) 8.3 Hz, 1 H), 3.90 (d, J ) 4.0 Hz, 1 H), 4.01 (dd, J )

7.6, 6.4 Hz, 1 H), 4.16 (ddd, J ) 8.4, 6.1, 5.1 Hz, 1 H), 4.34

(dd, J ) 8.8, 4.8 Hz, 1 H), 4.65 (dd, J ) 6.2, 3.3 Hz, 1 H), 4.93

(dd, J ) 6.1, 4.3 Hz, 1 H), 4.94-5.09 (m, 2 H), 5.77-5.92 (m,

1 H); ¹³C NMR (75 MHz, CDCl₃) δ -4.44 (CH₃), -4.04 (CH₃),

8.01 (CH₃), 8.21 (CH₃), 8.37 (CH₃), 8.43 (CH₃), 18.35 (C), 25.94

(CH₃), 26.44 (CH₂), 28.10 (CH₂), 28.68 (CH₂), 28.71 (CH₂), 29.64

(CH₂), 39.61 (CH₂), 66.57 (CH₂), 70.86 (CH), 80.11 (CH), 82.50

(CH), 84.50 (CH), 86.24 (CH), 113.14 (C), 114.84 (CH₂), 116.48

(C), 137.19 (CH), 206.44 (C); HRMS calcd for C₂₈H₅₀O₇Si (M

+ Na⁺) 549.3224, found 549.3211.

Recyclin g of 33b. Solid periodic acid (150 mg; 0.656 mmol;

1.2 equiv) was added at room temperature to a solution of 33b

(286 mg; 0.525 mmol) in THF (11 mL; 0.048 M). After 30 min,

dry Et₂O (3.2 mL) and Na₂SO₄(163 mg) were added, and

stirring was continued at room temperature for another 20

min. Slow filtration of the reaction mixture through a frit

funnel half full of Et₂O-saturated silica gel ensured complete

separation of the solid byproduct from the desired product.

Flash column chromatography (3:1 hexanes-Et₂O) provided

220 mg of lactone 32 (0.481 mmol; 92%) as a colorless oil that

solidified upon drying under vacuum. See data for 32 above.

P r ep a r a tion of Hyd r oxy Mesyla te 34. Diol 33a (211 mg;

0.387 mmol) and DMAP (2.5 mg; 0.20 mmol; 0.5 equiv) were

dissolved in CH₂Cl₂(3.9 mL; 0.10 M) at room temperature.

Triethylamine (0.17 mL; 1.2 mmol; 3.2 equiv) was added, and

the solution was cooled to -50 °C for the addition of MsCl (93

µL; 1.2 mmol; 3.0 equiv). Stirring was continued for 45 min,

keeping the temperature between -40 and -50 °C, at which

point the reaction mixture was quenched with water (5 mL)

and allowed to warm to room temperature. The layers were

partitioned, and the aqueous layer was extracted with CH₂-

Cl₂followed by washes of the combined organic layers with

0.6 N HCl, water, and saturated NaHCO₃. The organic layers

were then dried over MgSO₄, filtered, concentrated in vacuo,

and subjected to FCC (3:1 benzene-Et₂O) to give 156 mg of

hydroxy mesylate 34 (0.251 mmol; 64%) and 36 mg of

recovered 33a (0.066 mmol, 17%) as colorless oils. Data for

P r ep a r a tion of En oa te 37. A solution of pyranone 35 (36

mg; 0.068 mmol) in THF (2.3 mL; 0.030 M) was cooled to -78

°C for the dropwise addition of a 1.0 M solution of DIBALH in

PhCH₃(0.41 mL; 0.41 mmol; 6.0 equiv). The reaction mixture

was stirred for 3 h and was transferred into a freshly prepared

saturated solution of potassium sodium tartrate (5 mL). The

cloudy solution was allowed to warm to room temperature and

stir for 30 min, during which time it became clear, indicating

that all the aluminum salts had dissolved. Extraction with

Et₂O was followed by a brine wash of the ether layers, which

were then dried over MgSO₄, filtered and concentrated in

vacuo. FCC (2:1 hexanes-Et₂O) resulted in an 86% yield of

the desired alcohol (31 mg; 0.059 mmol). Data for the alcohol:

R_f0.25 (1:1 hexanes-Et₂O); [R]²³-2.25 (c 1.42, CHCl₃); IR

D

34: R_f0.27 (1:2 hexanes-Et₂O); [R]²³+1.3° (c 4.23, CHCl₃);

(thin film) 3449 (br), 1641 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ

D

Halichondrin B: Synthesis of the C(1)-C(15) Subunit

J . Org. Chem., Vol. 65, No. 13, 2000 4085

0.08 (s, 3 H), 0.12 (s, 3 H), 0.84-1.00 (m, 21 H), 1.55-1.86 (m,

10 H), 2.08 (d, J ) 10.4 Hz, OH), 3.43 (d, J ) 7.1 Hz, 1 H),

3.55 (atd, J ) 10.2, 2.3 Hz, 1 H), 3.74 (ddd, J ) 10.3, 7.3, 3.4

Hz, 1 H), 3.91 (at, J ) 7.7 Hz, 1 H), 3.96 (dd, J ) 7.8, 6.5 Hz,

1 H), 4.10 (dd, J ) 7.2, 2.3 Hz, 1 H), 4.29 (ddd, J ) 7.7, 6.5,

2.8 Hz, 1 H), 4.43 (m, 2 H), 4.93-5.09 (m, 2 H), 5.75-5.91 (m,

1 H); ¹³C NMR (75 MHz, CDCl₃) δ -4.50 (CH₃), -4.09 (CH₃),

7.97 (CH₃), 8.39 (CH₃), 8.46 (CH₃), 8.61 (CH₃), 18.11 (C), 25.96

(CH₃), 27.56 (CH₂), 27.75 (CH₂), 28.52 (CH₂), 29.03 (CH₂), 29.34

(CH₂), 31.65 (CH₂), 65.35 (CH₂), 68.65 (CH), 71.65 (CH), 72.03

(CH), 72.23 (CH), 72.71 (CH), 73.16 (CH), 76.39 (CH), 112.10

(C), 113.73 (CH₂), 114.53 (C), 138.60 (CH); HRMS calcd for

(CH₂), 28.01 (CH₂), 28.23 (CH₂), 29.40 (CH₂), 30.02 (CH₂), 30.65

(CH₂), 40.19 (CH₂), 51.49 (CH₃), 65.95 (CH₂), 65.97 (CH), 71.35

(CH), 72.25 (CH), 72.54 (CH), 73.66 (CH), 75.16 (CH), 76.56

(CH), 112.39 (C), 113.42 (C), 171.42 (C); HRMS calcd for

C₃₀H₅₄O₉Si (M + Na⁺) 609.3435, found 609.3455.

P r ep a r a tion of Alcoh ol 38. A 1.0 M solution of tetra-n-

butylammonium fluoride (0.15 mL; 0.15 mmol; 1.2 equiv) was

added dropwise to a solution of 31 (73 mg; 0.12 mmol) in THF

(1.2 mL; 0.10 M) at room temperature. The reaction mixture

was stirred for 24 h and was then directly applied to a silica

gel column and eluted with Et₂O. Evaporation of the solvent

in vacuo afforded 58 mg of alcohol 38 (0.12 mmol, 99%) as a

clear oil. Data for 38: R_f0.31 (1:2 hexanes-Et₂O); [R]²³_D-22.4°

C

₂₈H₅₂O₇Si (M + Na⁺) 551.3380, found 551.3404.

1

The alcohol from above (220 mg; 0.416 mmol) was added to

(c 1.86, CHCl₃); IR (thin film) 3529 (br), 1740 cm^-1; H NMR

a two-neck flask equipped with a gas inlet tube and a drying

tube with the aid of CH₂Cl₂(14 mL; 0.030 M). Nitrogen was

bubbled through the solution for 10 min, and it was cooled to

-78 °C. Ozone was bubbled through the solution until a blue

color persisted for 5 min. The reaction mixture was then

purged with nitrogen until the blue color dissipated, and Ph₃P

(218 mg; 0.832 mmol; 2 equiv) was added to quench. Stirring

was continued at -78 °C for 5 min, and the solution was then

allowed to warm to room temperature where it stirred for 1

h. Methyl(triphenylphosphoranylidene)acetate (1.39 g; 4.16

mmol; 10 equiv) was added, and stirring was continued

overnight at room temperature. The solvent was removed in

vacuo, and the crude residue was triturated with hexanes to

remove excess ylide and Ph₃P(O). The hexanes solution was

concentrated in vacuo, and the remaining residue was purified

by FCC (8:1 to 1:2 hexanes-Et₂O) to give 228 mg (0.389 mmol;

94%) of enoate 37 as a 12:1 mixture of (E):(Z) isomers. Data

(300 MHz, CDCl₃) δ 0.85-0.94 (m, 9 H), 1.00 (at, J ) 7.3 Hz,

3 H), 1.38-1.53 (m, 1 H), 1.56-1.70 (m, 7 H), 1.75-1.92 (m, 3

H), 2.08-2.19 (m, 1 H), 1.56-1.70 (m, 7 H), 1.75-1.92 (m, 3

H), 2.08-2.19 (m, 1 H), 2.44 (ABX, J _AB) 16.3 Hz, J _AX) 6.2

Hz, 1 H), 2.73 (ABX, J _AB) 16.2 Hz, J _BX) 7.1 Hz, 1 H), 3.43

(as, 1 H), 3.60 (dd, J ) 10.2, 2.8 Hz, 1 H), 3.68 (s, 3 H), 3.75

(d, J ) 6.7 Hz, 1 H), 3.84-3.96 (m, 3 H), 3.98 (ddd, J ) 10.5,

4.6 Hz, 1 H), 4.09-4.21 (m, 2 H), 4.50 (ABXY, J _AB) 8.5 Hz,

J _AX) 1.3 Hz, 1 H), 4.56 (ABXY, J _AB) 8.5 Hz, J _BY) 2.7 Hz,

1 H); ¹³C NMR (75 MHz, CDCl₃) δ 7.73 (CH₃), 7.99 (CH₃), 8.18

(CH₃), 8.64 (CH₃), 27.78 (CH₂), 28.30 (CH₂), 29.27 (CH₂), 29.62

(CH₂), 30.10 (CH₂), 30.44 (CH₂), 40.19 (CH₂), 51.62 (CH₃), 66.78

(CH), 67.85 (CH), 67.92 (CH₂), 72.02 (CH), 74.10 (CH), 74.80

(CH), 75.50 (CH), 76.48 (CH), 77.97 (CH), 112.96 (C), 114.60

(C), 171.43 (C); HRMS calcd for C₂₄H₄₀O₉(M + Na⁺) 495.2570,

found 495.2554.

P r ep a r a tion of Keton e 39. To a solution of alcohol 38 (27

mg; 0.057 mmol) in CH₂Cl₂(0.57 mL; 0.10 M) were added

tetra-n-propylammonium perruthenate (2 mg; 0.006 mmol; 0.1

equiv), N-methylmorpholine N-oxide (8.2 mg; 0.070 mmol; 1.2

equiv), and crushed 4 Å molecular sieves (7.3 mg). The reaction

mixture turned black within 5 min. After being stirred at room

temperature for 1.5 h, the mixture was filtered through a plug

of silica gel and rinsed with Et₂O. Removal of the solvent in

vacuo was followed by column chromatography (1:2 hexanes-

Et₂O) to afford 26 mg (0.055 mmol, 94%) of ketone 39 as a

clear oil that solidified upon drying under vacuum. Data for

39: R_f0.21 (1:2 hexanes-Et₂O); [R]²³_D+19.7° (c 1.43, CHCl₃);

IR (thin film) 1735 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 0.82-

1.01 (m, 12 H), 1.41-1.88 (m, 11 H), 2.09-2.20 (m, 1 H), 2.44

for 37: R_f0.17 (1:1 hexanes-Et₂O); [R]²³-18.0° (c 1.65,

D

CHCl₃); IR (thin film) 3450 (br), 1725, 1657 cm^-1

;

¹H NMR

(300 MHz, CDCl₃) δ 0.08 (s, 3 H), 0.12 (s, 3 H), 0.84-0.99 (m,

21 H), 1.55-1.80 (m, 9 H), 1.81-1.94 (m, 1 H), 2.08 (d, J )

10.7 Hz, OH), 2.25-2.51 (m, 2 H), 3.44 (d, J ) 7.1 Hz, 1 H),

3.49-3.58 (m, 1 H), 3.68-3.78 (m, 1 H), 3.72 (s, 3 H), 3.91 (at,

J ) 7.8 Hz, 1 H), 3.96 (dd, J ) 8.0, 6.6 Hz, 1 H), 4.08 (dd, J )

6.9, 2.9 Hz, 1 H), 4.28 (ddd, J ) 7.7, 6.7, 3.0 Hz, 1 H), 4.40-

4.47 (m, 2 H), 5.85 (dt, J ) 15.6, 1.5 Hz, 1 H), 6.99 (dt, J )

15.6, 6.9 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ -4.51 (CH₃),

-4.07 (CH₃), 7.96 (CH₃), 8.40 (CH₃), 8.45 (CH₃), 8.60 (CH₃),

18.10 (C), 25.93 (CH₃), 27.54 (CH₂), 27.61 (CH₂), 27.67 (CH₂),

28.53 (CH₂), 29.34 (CH₂), 30.84 (CH₂), 51.36 (CH₃), 65.42 (CH₂),

68.64 (CH), 71.66 (CH), 71.68 (CH), 72.26 (CH), 72.63 (CH),

72.98 (CH), 76.38 (CH), 112.17 (C), 113.82 (C), 121.06 (CH),

(ABX, J _AB) 16.2 Hz, J _AX) 6.1 Hz, 1 H), 2.73 (ABX, J _AB

)

16.2 Hz, J _BX) 7.0 Hz, 1 H), 3.44 (dd, J ) 10.3, 3.1 Hz, 1 H),

3.68 (s, 3 H), 3.80-3.90 (m, 1 H), 3.98 (ddd, J ) 10.8, 10.6, 4.8

Hz, 1 H), 4.08 (dd, J ) 8.2, 8.0 Hz, 1 H), 4.32 (at, J ) 8.1 Hz,

1 H), 4.33 (d, J ) 2.2 Hz, 1 H), 4.54 (dd, J ) 8.5, 3.0 Hz, 1 H),

4.78 (dd, J ) 8.3, 1.8 Hz, 1 H), 4.96 (at, J ) 8.0 Hz, 1 H); ¹³C

NMR (75 MHz, CDCl₃) δ 7.89 (CH₃), 8.10 (CH₃), 8.58 (CH₃),

27.30 (CH₂), 28.26 (CH₂), 28.71 (CH₂), 29.08 (CH₂), 29.87 (CH₂),

30.55 (CH₂), 40.09 (CH₂), 51.65 (CH₃), 65.79 (CH₂), 66.34 (CH),

71.10 (CH), 75.27 (CH), 75.34 (CH), 75.44 (CH), 78.91 (CH),

114.29 (C), 114.44 (C), 171.36 (C), 205.20 (C); HRMS calcd for

149.21 (CH), 167.07 (C); HRMS calcd for C₃₀H₅₄O₉Si (M⁺

Na) 609.3435, found 609.3428.

+

P r ep a r a tion of Ester 31. A 40% solution of benzyltri-

methylammonium methoxide in MeOH (0.57 mL; 1.2 mmol;

3.0 equiv) was added dropwise to a solution of 37 (228 mg;

0.388 mmol) in benzene (39 mL; 0.010 M) that had been cooled

to 5 °C. The reaction mixture was stirred at 5 °C for 10 min

and was then warmed to room temperature where it was

stirred for 3 h. Although 37 is consumed within 10 min at room

temperature, the additional stirring time is necessary to

ensure complete equilibration of the initially formed C(3) axial

isomer to the desired C(3) equatorial isomer. Quenching with

0.6 N HCl (15 mL) was followed by extraction of the aqueous

layer with Et₂O. The combined organic layers were washed

again with 0.6 N HCl and brine, dried over MgSO₄, filtered

and concentrated in vacuo. FCC (3:1 hexanes-Et₂O) of the

crude residue provided 167 mg (0.285 mmol; 73%) of ester 31

as a colorless oil. Data for 31: R_f0.33 (1:1 hexanes-Et₂O);

[R]²³_D+3.8° (c 3.28, CHCl₃); IR (thin film) 1742 cm^-1; ¹H NMR

(300 MHz, CDCl₃) δ 0.09 (s, 3 H), 0.10 (s, 3 H), 0.83-0.95 (m,

18 H), 1.00 (at, J ) 7.3 Hz, 3 H), 1.33-1.86 (m, 11 H), 2.03-

2.14 (m, 1 H), 2.42 (ABX, J _AB) 16.2 Hz, J _AX) 6.2 Hz, 1 H),

2.72 (ABX, J _AB) 16.2 Hz, J _BX) 7.0 Hz, 1 H), 3.49 (dd, J )

10.3, 2.5 Hz, 1 H), 3.51 (dd, J ) 7.3, 0.8 Hz, 1 H), 3.67 (s, 3 H),

3.78-3.99 (m, 4 H), 4.07 (dd, J ) 7.5, 3.8 Hz, 1 H), 4.22 (ddd,

J ) 8.0, 6.3, 3.9 Hz, 1 H), 4.43 (ABXY, J _AB) 8.7 Hz, J _AX) 0.3

Hz, 1 H), 4.46 (ABXY, J _AB) 8.7 Hz, J _BY) 2.1 Hz, 1 H); ¹³C

NMR (75 MHz, CDCl₃) δ -4.57 (CH₃), -3.95 (CH₃), 7.43 (CH₃),

8.25 (CH₃), 8.31 (CH₃), 8.62 (CH₃), 18.22 (C), 25.93 (CH₃), 27.95

C

₂₄H₃₈O₉(M + Na⁺) 493.2414, found 493.2422.

P r ep a r a tion of Keton e 39 a n d La cton e 40. To a solution

of alcohol 38 (117 mg; 0.248 mmol) in CH₂Cl₂(1.7 mL; 0.15

M) were added pyridinium chlorochromate (160 mg, 0.742

mmol, 3.0 equiv), sodium acetate (160 mg), and 4 Å molecular

sieves (198 mg) at room temperature. The reaction mixture

was stirred at room temperature for 48 h, and then Celite (124

mg) was added and stirring was continued for another 40 min.

The mixture was then filtered through a plug of Celite, and

the dark brown filtrate was concentrated in vacuo. FCC (1:2

hexanes-Et₂O) of this crude residue gave 60 mg of ketone 39

(52%; 0.13 mmol), 17 mg of recovered alcohol 38 (15%; 0.036

mmol), and 22 mg of lactone 40 (27%; 0.067 mmol), all as

colorless oils. Data for 38 and 39 shown above. Data for 40:

R_f0.18 (1:2 hexanes:Et₂O); IR (thin film) 1744 cm^-1; ¹H NMR

(300 MHz, CDCl₃) δ 0.94 (at, J ) 7.4 Hz, 3 H), 0.95 (at, J )

7.3 Hz, 3 H), 1.42-1.94 (m, 7 H), 2.30-2.39 (m, 1 H), 2.48

(ABX, J _AB) 16.1 Hz, J _AX) 5.7 Hz, 1 H), 2.74 (ABX, J _AB

)

16.1 Hz, J _BX) 7.1 Hz, 1 H), 3.55 (dd, J ) 9.6, 2.2 Hz, 1 H),

3.70 (s, 3 H), 3.94 (dddd, J ) 11.2, 7.7, 5.8, 2.1 Hz, 1 H), 4.55

4086 J . Org. Chem., Vol. 65, No. 13, 2000

Burke et al.

(ddd, J ) 10.9, 9.4, 4.9 Hz, 1 H), 4.60-4.67 (m, 2 H); ¹³C NMR

(75 MHz, CDCl₃) δ 7.74 (CH₃), 8.42 (CH₃), 28.87 (CH₂), 29.02

(CH₂), 29.29 (CH₂), 39.93 (CH₂), 51.78 (CH₃), 70.44 (CH), 73.31

(CH), 74.26 (CH), 75.17 (CH), 75.80 (CH), 116.36 (C), 167.60

(C), 171.08 (C); MS m/e (relative intensity, assignment) 299.1

(100, M⁺- C₂H₅).

50% aqueous MeOH (3 mL; 0.02 M). The cloudy reaction

mixture was stirred for 3 h and was subsequently poured into

water (5 mL) and extracted with CH₂Cl₂. The combined organic

layers were washed with brine, dried over Na₂SO₄, filtered,

concentrated in vacuo, and subjected to FCC (2:1 to 1:1

hexanes-Et₂O). Aldehyde 5 was isolated in 97% yield (29 mg;

0.060 mmol) as a stable white crystalline solid: R_f0.28 (1:1

P r ep a r a tion of Alcoh ol 41. To a slurry of ketone 39 (28

mg; 0.060 mmol) in pentane (1.2 mL) was added freshly

prepared zinc borohydride (0.16 M in Et₂O; 0.38 mL; 0.061

mmol; 1 equiv) at room temperature. The cloudy white mixture

stirred for 25 min at room temperature and was then quenched

with 0.6 N HCl (2 mL). The aqueous phase was extracted with

Et₂O, the combined organic phases were washed with water

and sat. NaHCO₃, dried over MgSO₄, and concentrated in

vacuo. FCC (1:2 hexanes-Et₂O) of the crude product afforded

22 mg (0.047 mmol, 78%) of an inseparable 14:1 mixture of

the C(11) epimeric alcohols 41 and 38 as a clear oil: R_f0.34

hexanes-Et₂O); [R]²⁴-52.5° (c 2.10, CHCl₃); IR (thin film)

D

1741 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 0.06 (s, 3 H), 0.08 (s,

3 H), 0.88-0.93 (m, 12 H), 1.00 (t, J ) 7.5 Hz, 3 H), 1.39-1.90

(m, 7 H), 2.02 (m, 1 H), 2.42 (ABX, J _AB) 16.4 Hz, J _AX) 5.9

Hz, 1 H), 2.72 (ABX, J _AB) 16.4 Hz, J _BX) 6.9 Hz, 1 H), 3.48

(dd, J ) 10.2, 2.6 Hz, 1 H), 3.67 (s, 3 H), 3.78 (dd, J ) 9.1, 1.5

Hz, 1 H), 3.79-3.97 (m, 2 H), 4.22 (dd, J ) 9.1, 2.2 Hz, 1 H),

4.47 (dd, J ) 8.4, 1.5 Hz, 1 H), 4.56 (dd, J ) 8.4, 2.6 Hz, 1 H),

9.70 (d, J ) 2.2 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ -5.47

(CH₃), -4.62 (CH₃), 7.80 (CH₃), 8.60 (CH₃), 18.13 (C), 25.60

(CH₃), 27.83 (CH₂), 28.54 (CH₂), 30.01 (CH₂), 30.46 (CH₂), 40.10

(CH₂), 51.56 (CH₃), 66.52 (CH), 71.26 (CH), 71.55 (CH), 73.54

(CH), 75.42 (CH), 75.52 (CH), 76.45 (CH), 114.12 (C), 171.34

(C), 201.53 (CH); HRMS calcd for C₂₄H₄₃O₈Si (M⁺+ H)

487.2727, found 487.2703.

(1:2 hexanes-Et₂O); IR (thin film) 3479 (br), 1740 cm^-^{1 1}H

;

NMR (300 MHz, CDCl₃) δ 0.85-0.95 (m, 9 H), 0.99 (at, J )

7.4 Hz, 3 H), 1.40-1.72 (m, 8 H), 1.74-1.87 (m, 3 H), 1.97-

2.07 (m, 1 H), 2.43 (ABX, J _AB) 16.1 Hz, J _AX) 6.2 Hz, 1 H),

2.48 (d, J ) 6.2 Hz, OH), 2.73 (ABX, J _AB) 16.2 Hz, J _BX) 6.8

Hz, 1 H), 3.51 (dd, J ) 10.4, 2.8 Hz, 1 H), 3.58 (dd, J ) 8.5,

1.4 Hz, 1 H), 3.68 (s, 3 H), 3.69 (ddd, J ) 8.3, 6.0, 4.4 Hz, 1 H),

3.81 (at, J ) 8.0 Hz, 1 H), 3.81-3.95 (m, 2 H), 4.03 (dd, J )

8.2, 6.7 Hz, 1 H), 4.22 (ddd, J ) 7.8, 6.4, 4.4 Hz, 1 H), 4.53

(dd, J ) 8.7, 2.6 Hz, 1 H), 4.63 (dd, J ) 8.6, 1.7 Hz, 1 H); ¹³C

NMR (75 MHz, CDCl₃) δ 7.53 (CH₃), 8.04 (CH₃), 8.68 (CH₃),

28.32 (CH₂), 28.49 (CH₂), 29.05 (CH₂), 29.63 (CH₂), 30.11 (CH₂),

30.45 (CH₂), 40.17 (CH₂), 51.59 (CH₃), 66.41 (CH), 66.80 (CH₂),

70.17 (CH), 71.02 (CH), 71.49 (CH), 74.28 (CH), 75.44 (CH),

76.71 (CH), 112.47 (C), 113.84 (C), 171.46 (C); HRMS calcd

for C₂₄H₄₀O₉(M + Na⁺) 495.2570, found 495.2592.

P r ep a r a tion of En on e 4. Aldehyde 5 (95 mg; 0.20 mmol)

and ylide 42 (250 mg; 0.590 mmol; 3 equiv) were combined

with PhCH₃(4 mL; 0.05 M) at room temperature and subse-

quently heated to a vigorous reflux for 3.5 h. The reaction

mixture was then cooled to room temperature, the solvent was

removed in vacuo, and the crude residue was dissolved in

minimal CH₂Cl₂and applied directly to a column for FCC (2:1

to 1:1 hexanes-Et₂O) to give 130 mg of enone 4 (0.206 mmol;

100%): R_f0.24 (1:1 hexanes-Et₂O); [R]²⁴-26.3° (c 2.50,

D

1

CHCl₃); IR (thin film) 1741, 1715 cm^-1; H NMR (300 MHz,

CDCl₃) δ 0.00 (s, 3 H), 0.08 (s, 3 H), 0.85-0.93 (m, 12 H), 0.99

(t, J ) 7.4 Hz, 3 H), 1.36-1.94 (m, 8 H), 2.41 (ABX, J _AB

16.2 Hz, J _AX) 5.9 Hz, 1 H), 2.70 (ABX, J _AB) 16.2 Hz, J _BX

)

P r ep a r a tion of Silyl Eth er 30. To a solution of the 14:1

mixture of 41:38 (40 mg; 0.085 mmol) in N,N-dimethylform-

amide (0.12 mL; 0.71 M) were added imidazole (57 mg; 0.84

mmol; 10 equiv) and tert-butyldimethylsilyl chloride (64 mg;

0.42 mmol; 5 equiv). The resulting solution was stirred at room

temperature for 48 h. Dilution with water (2 mL) was followed

by extraction with Et₂O. The combined organic layers were

washed with water and brine, dried over MgSO₄, filtered, and

concentrated in vacuo. FCC (3:1 hexanes-Et₂O) of the crude

product afforded 32 mg (0.055 mmol; 81%) of silyl ether 30

and 3 mg (0.005 mmol; 6%) of silyl ether 31 as clear colorless

oils. Data for 30 and 31 are shown above.

7.0 Hz, 1 H), 3.39-3.44 (m, 2 H), 3.66 (s, 3 H), 3.78-3.89 (m,

2 H), 4.24 (s, 2 H), 4.39 (ddd, J ) 8.5, 5.0, 1.3 Hz, 1 H), 4.50

(m, 2 H), 4.60 (s, 2 H), 6.48 (dd, J ) 16.2, 1.3 Hz, 1 H), 7.08

(dd, J ) 16.2, 5.0 Hz, 1 H), 7.29-7.37 (m, 5 H); ¹³C NMR (75

MHz, CDCl₃) δ -5.29 (CH₃), -4.28 (CH₃), 7.76 (CH₃), 8.59

(CH₃), 17.95 (C), 25.69 (CH₃), 27.79 (CH₂), 28.54 (CH₂), 29.97

(CH₂), 30.39 (CH₂), 40.08 (CH₂), 51.48 (CH₃), 66.44 (CH), 70.42

(CH), 71.68 (CH), 73.13 (CH₂), 73.61 (CH), 73.89 (CH₂), 74.18

(CH), 75.35 (CH), 76.48 (CH), 113.89 (C), 125.22 (CH), 127.80

(CH), 127.83 (CH), 128.32 (CH), 137.16 (C), 148.89 (CH),

171.30 (C), 196.85 (C); HRMS calcd for C₃₄H₅₂O₉Si (M⁺)

632.3380, found 632.3392.

P r ep a r a tion of Ald eh yd e 5. Acetal 30 (183 mg; 0.312

mmol) was dissolved in an 80% solution of AcOH in water (31

mL; 0.010 M) and was stirred at room temperature for 20 h.

The reaction mixture was then transferred to a large round-

bottom flask with the aid of CH₂Cl₂and water (∼5 mL of each),

and the acetic acid was carefully neutralized with solid K₂-

CO₃. This mixture was exhaustively extracted with CH₂Cl₂,

and the combined organic layers were washed with brine, dried

over MgSO₄, filtered, and concentrated in vacuo. The crude

residue was purified by FCC (2:1 to 1:2 hexanes-Et₂O, then

100% Et₂O) to afford 112 mg of the terminal 1,2-diol (0.215

mmol; 69%) and 24 mg recovered 30 (0.041 mmol; 13%). Data

P r ep a r a tion of Ca ged Keta l 3 a n d Meth yl Keton e 43.

Enone 4 (9 mg, 0.01 mmol) was dissolved at room temperature

in a mixture of CH₃CN (1.2 mL) and 52% aqueous HF (0.12

mL) in a small plastic bottle. After being stirred at 22 °C for

27 h, the solution was poured into water (5 mL) and extracted

with CH₂Cl₂. The combined extracts were dried over MgSO₄,

filtered, and concentrated in vacuo. FCC gave caged ketal 3

(3 mg; 0.007 mmol; 49%) and methyl ketone 43 (1-2 mg;

0.004-0.006 mmol; 30-40%). Data for 3: R_f0.37 (Et₂O); [R]²⁴

D

-34.0° (c 0.685, CHCl₃); IR (thin film) 1739 cm^-1

;

¹H NMR

(300 MHz, CD₃OD) δ 1.23-1.47 (m, 2 H), 1.73 (m, 1 H), 1.98

(d, J ) 13.4 Hz, 1 H), 2.04 (m, 1 H), 2.24 (dd, J ) 13.4, 5.0 Hz,

1 H), 2.41 (ABX, J _AB) 16.2 Hz, J _AX) 4.2 Hz, 1 H), 2.48 (ABX,

J _AB) 16.2 Hz, J _BX) 8.4 Hz, 1 H), 2.97 (dd, J ) 9.6, 1.8 Hz, 1

H), 3.61-3.66 (m, 5 H), 3.81 (m, 1 H), 4.14 (dd, J ) 6.5, 3.9

Hz, 1 H), 4.20 (dd, J ) 6.5, 4.5 Hz, 1 H), 4.25 (ddd, J ) 10.0,

9.6, 4.4 Hz, 1 H), 4.39 (dd, J ) 3.9, 1.8 Hz, 1 H), 4.59 (AB, J _AB

) 12.2 Hz, ∆υ_AB) 27.6 Hz, 1 H), 4.65 (dd, J ) 4.5, 4.4 Hz, 1

H), 4.69 (AB, J _AB) 12.2 Hz, ∆υ_AB) 27.6 Hz, 1 H), 4.71 (dd, J

) 5.0, 4.4 Hz, 1 H), 7.26-7.36 (m, 5 H); ¹³C NMR (75 MHz,

CD₃OD) δ 31.13 (CH₂), 31.43 (CH₂), 41.11 (CH₂), 44.89 (CH₂),

52.14 (CH₃), 69.60 (CH), 73.07 (CH₂), 74.61 (CH₂), 75.09 (CH),

76.01 (CH), 76.60 (CH), 77.98 (CH), 79.33 (CH), 82.06 (CH),

83.88 (CH), 110.88 (C), 128.60 (CH), 128.75 (CH), 129.12 (CH),

129.32 (CH), 129.45 (CH), 139.64, (C) 173.25 (C); HRMS calcd

for C₂₃H₂₈O₈(M⁺) 432.1784, found 432.1783. Data for methyl

ketone 43: R_f0.16 (Et₂O); IR (KBr pellet) 3409 (br), 1774, 1729,

1728 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 1.30-1.60 (m, 2 H +

for diol: R_f0.34 (Et₂O); [R]²⁴-13.0° (c 3.15, CHCl₃); IR (thin

D

film) 3442 (br), 1740 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 0.12

(s, 6 H), 0.87 (s, 9 H), 0.91 (t, J ) 7.3 Hz, 3 H), 0.99 (t, J ) 7.3

Hz, 3 H), 1.35-1.85 (m, 7 H), 2.00 (m, 1 H), 2.43 (ABX, J _AB

)

16.2 Hz, J _AX) 5.9 Hz, 1 H + OH), 2.72 (ABX, J _AB) 16.2 Hz,

J _BX) 6.9 Hz, 1 H), 3.30 (br s, OH), 3.50 (dd, J ) 10.2, 2.6 Hz,

1 H), 3.64 (s, 3 H), 3.64-3.98 (m, 7 H), 4.05 (dd, J ) 8.9, 3.0

Hz, 1 H), 4.40 (dd, J ) 8.9, 1.3 Hz, 1 H), 4.53 (dd, J ) 8.6, 2.3

Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃) δ -5.05 (CH₃), -4.77

(CH₃), 7.67 (CH₃), 8.59 (CH₃), 17.92 (C), 25.74 (CH₃), 27.94

(CH₂), 28.45 (CH₂), 29.99 (CH₂), 30.51 (CH₂), 40.01 (CH₂), 51.54

(CH₃), 63.11 (CH₂), 66.80 (CH), 69.40 (CH), 71.45 (CH), 72.25

(CH), 73.71 (CH), 74.03 (CH), 75.42 (CH), 76.23 (CH), 114.02

(C), 171.23 (C); HRMS calcd for C₂₃H₄₁O₉Si (M⁺- C₂H₅)

489.2520, found 489.2530.

Sodium periodate (26 mg; 0.12 mmol; 2 equiv) was added

to a solution of the diol from above (34 mg; 0.066 mmol) in

Halichondrin B: Synthesis of the C(1)-C(15) Subunit

J . Org. Chem., Vol. 65, No. 13, 2000 4087

OH), 1.68 (m, 1 H), 2.02 (m, 1 H), 2.04 (s, 3 H), 2.39 (ABX, J _AB

) 12.0 Hz, J _AX) 3.8 Hz, 1 H), 2.43 (ABX, J _AB) 12.0 Hz, J _BX

) 6.3 Hz, 1 H), 2.69 (dd, J ) 14.0, 6.0 Hz, 1 H), 2.83 (dd, J )

14.0, 3.8 Hz, 1 H), 2.97 (dd, J ) 7.8, 1.8 Hz, 1 H), 3.54 (td, J

) 7.8, 4.0 Hz, 1 H), 3.56 (s, 3 H), 3.75 (m, 1 H), 4.21 (dd, J )

3.6, 1.8 Hz, 1 H), 4.32 (dd, J ) 6.6, 3.6 Hz, 1 H), 4.52 (dd, J )

6.0, 3.8 Hz, 1 H), 4.71 (d, J ) 6.6 Hz, 1 H); ¹³C NMR (75 MHz,

CDCl₃) δ 28.61 (CH₂), 30.06 (CH₂), 30.14 (CH₃), 40.33 (CH₂),

45.70 (CH₂), 51.71 (CH₃), 64.83 (CH), 69.50 (CH), 72.05 (CH),

73.71 (CH), 74.36 (CH), 75.85 (CH), 76.97 (CH), 171.15 (C),

204.54 (C), 212.58 (C); MS (FAB) m/e (relative intensity,

assignment) 365 (100, M + Na⁺).

combined organic layers were washed with saturated NaHCO₃,

brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.

FCC of the crude residue (1:2 hexanes-Et₂O) gave the furan

47 in 78% yield as a colorless oil (7 mg; 0.02 mmol). Data for

47: R_f0.38 (100% Et₂O); IR (thin film) 3463 (br), 1738, 1640,

1

1562 cm^-1; H NMR (500 MHz, C₆D₆) δ 0.89-1.02 (m, 1 H),

1.19-1.37 (m, 2 H), 1.84-1.90 (m, 2 H), 2.05 (dd, J ) 15.3,

5.7 Hz, 1 H), 2.23 (ap dq, J ) 8.7, 1.0 Hz, 2 H), 2.35 (br s,

OH), 2.37 (dd, J ) 15.3, 8.7 Hz, 1 H), 2.50 (ap t, J ) 2.7 Hz,

1 H), 2.85 (dd, J ) 9.3, 2.7, 1 H), 3.35 (s, 3 H), 3.54 (ddd, J )

10.8, 9.3, 5.7 Hz, 1 H), 3.67 (m, 1 H), 3.95 (dd, J ) 9.3, 2.7 Hz,

1 H), 4.09 (t, J ) 2.7 Hz, 1 H), 4.66 (d, J ) 9.3 Hz, 1 H), 4.87-

4.98 (m, 2 H), 5.62-5.74 (m, 1 H), 5.85 (d, J ) 3.3 Hz, 1 H),

6.31 (d, J ) 3.3 Hz, 1 H); ¹³C NMR (75 MHz, C₆D₆) δ 27.58

(CH₂), 28.78 (CH₂); 30.44 (CH₂), 31.83 (CH₂), 40.56 (CH₂), 51.76

(CH₃), 69.04 (CH), 69.49 (CH), 70.06 (CH), 72.02 (CH), 74.45

(CH), 78.67 (CH), 105.86 (CH), 110.44 (CH), 115.22 (CH₂),

137.52 (CH), 149.73 (C), 156.33 (C), 171.38 (C); MS (FAB) m/e

(relative intensity, assignment) 367 (20, M⁺+ H).

P r ep a r a tion of En on e 45. The aldehyde 5 (132 mg; 0.272

mmol) was dissolved in PhCH₃(10 mL; 0.027 M), and a

solution of ylide 44 (200 mg; 0.559 mmol; 2 equiv) in PhCH₃

(5 mL) was added to it. The resulting reaction mixture was

heated to a vigorous reflux for 3 h. The solvent was removed

in vacuo, and the crude residue was purified by FCC (3:1 to

1:1 hexanes-Et₂O) to provide 147 mg (0.260 mmol; 94%) of

enone 45. Data for 45: R_f0.38 (1:1 hexanes-Et₂O); IR (thin

1

film) 1740, 1699, 1676, 1638 cm^-1; H NMR (500 MHz, C₆D₆)

Ack n ow led gm en t. We gratefully acknowledge sup-

port of this work provided by NIH (grant CA 74394).

Graduate fellowships from Bristol-Myers Squibb (K.W.J.)

and an NIH CBI Training Grant (5 T32 GM08505,

W.T.L.) are also acknowledged, as is a Pfizer Under-

graduate Fellowship (J .J .K.) The NIH (ISIO RRO 8389-

01), NSF (CHE-9208463), and the Chemistry Depart-

ment of University of WisconsinsMadison are

acknowledged for NMR facility support.

δ 0.06 (s, 3 H), 0.17 (s, 3 H), 0.80 (t, J ) 8.2 Hz, 3 H), 1.02 (s,

9 H), 1.06 (t, J ) 7.9 Hz, 3 H), 1.13-1.26 (m, 2 H), 1.44-1.54

(m, 2 H), 1.75-1.85 (m, 3 H), 2.01 (dd, J ) 15.6, 5.7 Hz, 1 H),

2.30-2.50 (m, 6 H), 3.00 (dd, J ) 10.2, 3.3 Hz, 1 H), 3.26 (d,

J ) 9.0 Hz, 1 H), 3.31 (s, 3 H), 3.74 (m, 1 H), 3.99 (td, J )

10.2, 5.7 Hz, 1 H), 4.19 (dd, J ) 9.3, 3.3 Hz, 1 H), 4.34 (d, J )

9.3 Hz, 1 H), 4.54 (ddd, J ) 9.0, 4.5, 1.8 Hz, 1 H), 4.90-5.03

(m, 2 H), 5.67-5.82 (m, 1 H), 6.47 (dd, J ) 15.6, 1.8 Hz, 1 H),

7.09 (dd, J ) 15.6, 4.5 Hz, 1 H); MS (FAB) m/e (relative

intensity, assignment) 567 (100, M⁺+ H), 537 (83, M⁺- C₂H₅),

509 (67, M⁺- C₄H₉).

P r ep a r a tion of F u r a n 47. To a small plastic bottle was

added enone 45 (13 mg; 0.023 mmol) and CH₃CN (2 mL; 0.01

M). A 52% aqueous solution of hydrofluoric acid (0.2 mL) was

added slowly to the enone solution, and the resulting reaction

mixture was stirred at room temperature for 24 h. It was then

poured into water (2 mL) and extracted with CH₂Cl₂. The

Su p p or tin g In for m a tion Ava ila ble: Experimental pro-

cedures for preparation of rac-20, rac-21, 24, (S)-20, 6(S)-21,

42 and 44; ¹H and/or ¹³C NMR spectra for compounds 3-6, 8,

11, 13, 14, rac-20, rac-21, 22a , 22b, 23, 25, 27-41, 43, 45,

47, and unnumbered intermediates. This material is available

free of charge via the Internet at http://pubs.acs.org.

J O000140R

Article Doi

Halichondrin B: Synthesis of the C(1)-C(15) subunit

DOI: 10.1021/jo000140r

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Article abstract of DOI:10.1021/jo000140r

Full text of DOI:10.1021/jo000140r

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