Synthesis of unit A of cryptophycin via a [2,3]-Wittig rearrangement

Article abstract of DOI:10.1021/jo9815958

The synthesis of unit A of the cryptophycins from (S)-trans-3-penten-2- ol and from (S)-trans-4-hexen-3-ol has been completed. The key stereodetermining step is a [2,3]-Wittig rearrangement of a propargyl ether. Elaboration of the rearrangement product was accomplished by means of a selective hydroboration-oxidation of a terminal alkyne, Horner-Emmons homologation of the derived aldehyde, followed by selective ozonolytic cleavage and Wittig olefination. This synthesis provides easy access to the series of cryptophycin analogues that incorporate a modified aromatic ring in unit A.

Full text of DOI:10.1021/jo9815958

J . Org. Chem. 1999, 64, 1459-1463
1459
Syn th esis of Un it A of Cr yp top h ycin via a [2,3]-Wittig
Rea r r a n gem en t
J ian Liang,† David W. Hoard,‡ Vien Van Khau,‡ Michael J . Martinelli,*,‡ Eric D. Moher,‡
Richard E. Moore,*,† and Marcus A. Tius*,†
Chemical Process Research and Development, Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, Indiana 46285, and Department of Chemistry, 2545 The Mall, University of Hawaii,
Honolulu, Hawaii 96822
Received August 5, 1998
The synthesis of unit A of the cryptophycins from (S)-trans-3-penten-2-ol and from (S)-trans-4-
hexen-3-ol has been completed. The key stereodetermining step is a [2,3]-Wittig rearrangement of
a propargyl ether. Elaboration of the rearrangement product was accomplished by means of a
selective hydroboration-oxidation of a terminal alkyne, Horner-Emmons homologation of the
derived aldehyde, followed by selective ozonolytic cleavage and Wittig olefination. This synthesis
provides easy access to the series of cryptophycin analogues that incorporate a modified aromatic
ring in unit A.
The cryptophycins are a group of potent tumor-selec-
tive cytotoxins associated with the terrestrial blue-green
algae Nostoc sp. GSV 2241 and Nostoc sp. ATCC 53789.2
Compounds related to the cryptophycins, the arenast-
atins, were also isolated from an Okinawan sponge.
Arenastatin A was identical with cryptophycin 24, one
of the minor isolates from GSV 224.3 The first total
synthesis of cryptophycin 1 was carried out at the
University of Hawaii and served to determine the relative
and absolute stereochemistry.4 The retrosynthetic analy-
sis of the cryptophycins is straightforward because the
molecule is composed of four units. Unit A is an unsatur-
ated δ-hydroxy acid, unit B is a chlorinated D-tyrosine
derivative, whereas units C and D are (R)-(-)-2-methyl-
â-alanine and (S)-(-)-leucic acid, respectively.
strategy for the synthesis of unit A based on the anionic
Wittig rearrangement, starting with a single enantiomer
of a secondary allylic alcohol.
Nakai and Mikami’s thorough study of the [2,3]-Wittig
rearrangement provided ample support for our plan.7 The
stereoselectivity of the rearrangement can be predicted
on the basis of a five-membered cyclic transition state.
For example, Wittig rearrangement of E-ether 1 (R) H)
led in good yield and excellent selectivity to anti alcohol
3 (eq 1).8 The Z-isomer of 1 (R ) TMS) showed a
preference for syn product 2. In the homochiral series,
transfer of asymmetry is reported to take place efficiently.
The synthesis of unit A represents the greatest chal-
lenge. Our first cryptophycin synthesis described a
strategy for the preparation of unit A based on the
Sharpless asymmetric epoxidation.5 Since then, several
total syntheses and formal total syntheses of cryptophy-
cin have been published.6 We conceived an attractive
(5) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 101, 5974-
5976.
(6) (a) Salamonczyk, G. M.; Han, K.; Guo, Z.; Sih, C. J . J . Org. Chem.
1996, 61, 6893-6900. (b) Rej, R.; Nguyen, D.; Go, B.; Fortin, S.;
Lavalle´e, J .-F. J . Org. Chem. 1996, 61, 6289-6295. (c) Ali, S. M.; Georg,
G. I. Tetrahedron Lett. 1997, 38, 1703-1706. (d) Gardinier, K. M.;
Leahy, J . W. J . Org. Chem. 1997, 62, 7098-7099. (e) Dhokte, U. P.;
Khau, V. V.; Hutchison, D. R.; Martinelli, M. J . Tetrahedron Lett. 1998,
39, 8771-8774. (f) Furuyama, M.; Shimizu, I. Tetrahedron: Asymmetry
1998, 9, 1351-1357. (g) Kobayashi, M.; Kurosu, M.; Wang, W.;
Kitagawa, I. Chem. Pharm. Bull. 1994, 42, 2394-2396. (h) White, J .
D.; Hong, J .; Robarge, L. A. Tetrahedron Lett. 1998, 39, 8779-8782.
(i) Fray, A. H. Tetrahedron: Asymmetry 1998, 39, 2777-2782. (j)
Norman, B. H.; Hemscheidt, T.; Schultz, R. M.; Andis, S. L. J . Org.
Chem. 1998, 63, 5288-5294. Note: g and h describe arenastatin
syntheses.
† University of Hawaii.
‡ Eli Lilly and Company.
(1) Trimurtulu, G.; Ohtani, I.; Patterson, G. M. L.; Moore, R. E.;
Corbett, T. H.; Valeriote, F. A.; Demchik, L. J . Am. Chem. Soc. 1994,
116, 4729-4737.
(2) Schwartz, R. E.; Hirsch, C. F.; Sesin, D. F.; Flor, J . E.; Chartrain,
M.; Fromtling, R. E.; Harris, G. H.; Salvatore, M. J .; Liesch, J . M.;
Yudin, K. J . Ind. Microbiol. 1990, 5, 113-24.
(3) Kobayashi, M.; Aoki, S.; Ohyabu, N.; Kurosu, M.; Wang, W.;
Kitagawa, I. Tetrahedron Lett. 1994, 35, 7969-7972.
(4) Barrow, R. A.; Hemscheidt, T.; Liang, J .; Paik, S.; Moore, R. E.;
Tius, M. A. J . Am. Chem. Soc. 1995, 117, 2479-2490.
(7) Nakai, T.; Mikami, K. Org. React. 1994, 46, 105-209. See also:
Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885-902. Marshall, J . A.
In Comprehensive Organic Synthesis; Pattenden, G., Ed.; Pergamon:
London, 1991; Vol. 3, pp 975-1014.
10.1021/jo9815958 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/05/1999

1460 J . Org. Chem., Vol. 64, No. 5, 1999
Liang et al.
Sch em e 1a
For example, (Z)-allyl propargyl ether 1 (R ) TMS) of
98% ee rearranges to a 99/1 mixture of 2 and 3 in 64%
yield with no loss in optical purity for the major product.8a
Our analysis of the problem led us to consider prop-
argyl ether 4 as an attractive starting material (eq 2).
On the basis of published work, rearrangement of the
propargyl anion derived from 4 was expected to lead
selectively to anti alcohol 5.7 In our first attempt to put
this into practice, phenyl propenyl ketone was reduced
with sodium borohydride in methanol, in the presence
of cerous chloride,9 and the resulting alcohol was then
alkylated under phase-transfer conditions with propargyl
bromide to produce (()-4 in excellent overall yield.
Treatment of 4 with n-butyllithium failed to furnish any
of the desired product 5, but instead gave a mixture of
tertiary alcohol 6 and phenone 7 (ca. 1/2.5). Alcohol 6 was
apparently the product of a competing [1,2]-Wittig rear-
rangement of a benzylic carbanion. Rearrangement of the
same carbanion through a vinylogous process can ratio-
nalize the formation of ketone 7. An attempt was made
to suppress benzylic deprotonation by employing the
more hindered alkyllithium bases, phenyllithium or tert-
butyllithium, but both bases also produced 6 and 7 as
the major reaction products. The route was therefore
modified.
The starting point for the successful synthesis of unit
A was (S)-trans-3-penten-2-ol 8 (Scheme 1). This material
was prepared in greater than 95% ee10 by kinetic resolu-
tion of the racemate. Commercially available porcine
pancreatic lipase was used to trans-esterify racemic 8
with trifluoroethyl laurate.11 Volatile allylic alcohol 8 was
distilled from the reaction mixture and was converted to
propargyl ether 9 in 86% yield under phase-transfer
conditions.12 The Wittig rearrangement was accomplished
by treatment of 9 with an excess of n-butyllithium in THF
a
Key: (a) propargyl bromide, 50% aqueous NaOH, n-Bu4NHSO4
(cat.); 86%; (b) n-BuLi, THF, -90 °C to rt; 71%; (c) TBDPSCl, DMF,
imidazole; 92%; (d) 2-methyl-2-butene, BH3, THF, 0 °C; H2O2,
aqueous KH2PO4/K2HPO4 (2.2 M), 0 °C; 83%; (e) trimethyl
phosphonoacetate, tetramethylguanidine, THF, -78 °C; 92%; (f)
O3, CH2Cl2, pyridine, -78 °C; Zn, AcOH; 85%; (g) PhCHdPPh3,
THF, -78 °C to rt; PhSH, VAZO 88, PhMe, reflux; 82%; (h)
aqueous HF, CH3CN, rt; 93%.
at -90 °C, followed by slow warming to room tempera-
ture.13 The butyllithium was delivered in hexane, which
was evaporated under vacuum and replaced with THF.14
The desired (3R,4R)-4-methylhept-5(E)-en-1-yn-3-ol 10
was isolated as a 9/1 mixture with a diastereoisomer in
71% yield. The ratio of products was estimated by
1
integration of the propargylic methine signals in the H
NMR spectrum of the crude reaction product. Separation
of the two diastereoisomers was accomplished by careful
column chromatography on silica gel to furnish 10 (g95%
ee).
The next task was to functionalize the acetylenic
terminus of 10. Protection as the tert-butyldiphenylsilyl
(TBDPS) ether was followed by selective monohydrobo-
ration of the terminal alkyne with disiamylborane, which
was prepared in situ from 2-methyl-2-butene.15 Aldehyde
(12) Freedman, H. H.; Dubois, R. A. Tetrahedron Lett 1975, 16,
3251-3254.
(13) (a) Mikami, K.; Nakai, T. Synthesis, 1991, 594-604. (b) Wu,
H. J .; Ying, F.-H.; Shao, W. D. J . Org. Chem. 1995, 60, 6168-6172. (c)
Tsai, D. J .-S.; Midland, M. M. J . Org. Chem. 1984, 49, 1842-1843.
(14) This solvent change is essential for the stereoselectivity of the
rearrangement.
(15) (a) Brown, H. C. In Organic Synthesis via Boranes; J ohn Wiley
& Sons: New York, 1975; pp 15-35. (b) Zweifel, G.; Ayyangar, N. R.;
Brown, H. C. J . Am. Chem. Soc. 1963, 85, 2072-2075. (c) Baboule´ne,
M.; Lattes, A.; Benmaarouf-Khallaayoun, Z. Synth. Commun. 1990,
20, 2091-2096. (d) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M.
Tetrahedron Lett. 1989, 30, 1483-1486. (e) Holan, G.; O’Keefe, D. F.
Tetrahedron Lett. 1973, 14, 673-674. (f) Cha, J . S.; Min, J . S.; Kim, J .
M.; Kwon, O. O. Tetrahedron Lett. 1993, 34, 5113-5116.
(8) (a) Mikami, K.; Azuma, K.-I.; Nakai, T. Tetrahedron 1984, 40,
2303-2308. (b) Mikami, K.; Azuma, K.; Nakai, T. Chem. Lett. 1983,
1379-1382. (c) Sayo, N.; Kitahara, E.; Nakai, T. Chem. Lett. 1984,
259-262.
(9) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454-
5459.
(10) Enantiomeric excess was determined by analysis of the 1H NMR
spectrum of the Mosher ester. See: Dale, J . A.; Dull, D. L.; Mosher,
H. S. J . Org. Chem. 1969, 34, 2543-2549.
(11) Morgan, B.; Oehlschlager, A. C.; Stokes, T. M. J . Org. Chem.
1992, 57, 3231-3236.

Synthesis of Unit A of Cryptophycin
J . Org. Chem., Vol. 64, No. 5, 1999 1461
12 was produced in 83% yield. The TBDPS ether was
chosen instead of the tert-butyldimethylsilyl, which was
used in our first synthesis,4 so as to render 11 and 12
less volatile. The hydroboration could also be accom-
plished with catecholborane. Oxidative workup of the
intermediate vinyl borane was carried out with hydrogen
peroxide in a phosphate solution buffered at pH 7. In the
absence of buffer, mixtures of 12 and of the R,â-unsatur-
ated aldehyde derived from elimination of the â-silyloxy
group were formed. On larger scale, it was found that
saturated aqueous sodium acetate could also be used
during the oxidation of the borane. Carbon atoms 1 and
2 of unit A were introduced by means of a Horner-
Emmons reaction that led stereospecifically to the E
isomer of ester 13.16 Selective ozonolysis of the unconju-
gated alkene of 13 took place at -78 °C in dichlo-
romethane containing a small amount of pyridine.17
Reductive workup of the ozonide with zinc and acetic acid
led to aldehyde 14 in 85% overall yield from 13. Addition
of Sudan 7B as an indicator made it possible to follow
the progress of the ozonolysis by monitoring the disap-
pearance of the red color of the dye.18 The synthesis of
unit A in protected form was completed by first exposing
14 to benzyltriphenylphosphonium ylide19 and then
treating the mixture of (E)- and (Z)-styryl isomers (ca.
4/1) with thiophenol and 1,1′-azobis(cyclohexanecarbo-
nitrile) (VAZO 88) in refluxing toluene20 to give E isomer
15 as the exclusive product. The overall yield for this
process was 82% from 14. Fluorodesilylation of 15 led to
alcohol 16 in high yield. The physical data for 16 were
identical with those reported for this compound in our
first synthesis.4
diethylzinc, in the presence of 1 mol % (S)-1-piperidino-
3,3-dimethyl-2-butanol 18 (68.5% ee).23 Under these
conditions, 19 was formed in 64% yield from 2.41 mol of
17 in 83% ee. The addition reaction exhibits asymmetric
amplification, but the effect of catalyst ee on product
enantioselectivity also appears to be attenuated. For
example, when 18 of 98% ee was used in the reaction,
the ee of 19 improved to 86%, a difference of only 3%.
The Noyori group has reported a higher ee (90%) for
alcohol 19 in this reaction. Fortunately, the erosion in
optical purity of 19 was of little consequence to the
synthesis (vide infra). Unit A was prepared from 19 by
following the same sequence of reactions as summarized
in Scheme 1. Yields for the two syntheses of unit A,
starting from 8 or from 19, were identical within a few
percent at each step. For reasons that are not clear, the
diastereoselectivity of the [2,3]-Wittig rearrangement of
the propargyl ether derived from 19 was ca. 10% lower
than for 9. This may reflect subtle differences in transi-
tion state energies for the rearrangement. This result,
and also the failure of 4 to undergo successful Wittig
rearrangement, underscores the sensitivity of this process
to seemingly minor structural modification of the sub-
strate, a factor that deserves consideration during the
planning of a synthesis. Coupling of unit A, which was
derived from 19, with unit B led to chromatographically
separable diastereomers. Unit B, which was easily pre-
pared in high enantiomeric purity, thus served as a
resolving agent for unit A.
In conclusion, a successful synthesis of cryptophycin
unit A by means of a [2,3]-Wittig rearrangement has been
completed. Introduction of the phenyl group at the end
of the synthetic sequence has provided convenient access
to a large number of cryptophycin analogues that incor-
porate modifications in the aromatic ring of unit A. The
synthesis and the properties of those analogues will be
discussed in future publications.
The preparation of 8 by means of the enzymatic kinetic
resolution was inconvenient to scale-up. This prompted
us to develop an alternative starting material for the
synthesis that was much easier to prepare on a multi-
molar scale, but at the cost of some erosion in optical
purity. Since the double bond in 8 is ozonized in the
penultimate step of the synthesis, trans-(S)-4-hexen-3-
ol 1921 (eq 3) can serve equally well as the starting
material for unit A. This material was prepared according
Exp er im en ta l Section
1H NMR and 13C NMR spectra were recorded at 300 MHz
1H or 75 MHz 13C in deuteriochloroform (CDCl3) with chloro-
form as an internal reference, unless noted otherwise. 1H and
13C chemical shift assignments are based on detailed analysis
of two-dimensional NMR spectra when necessary. IR spectra
were recorded neat. MS data are reported in the form of m/z.
TLC was performed on EM Reagents precoated silica gel 60
F-254 analytical plates (0.25 mm). Normal-phase flash column
chromatography was performed on Brinkmann silica gel
(0.040-0.063 mm). Reversed-phase column chromatography
was performed on YMC-GEL ODS-A (120A, I-63/210 mm)
silica. Purity and homogeneity of all materials were deter-
mined chromatographically and from 1H and 13C NMR or
combustion analysis. THF and ethyl ether were distilled from
sodium-benzophenone ketyl. Methylene chloride was distilled
from phosphorus pentoxide and hexane from calcium hydride.
Other reagents were obtained commercially and used as
received unless otherwise specified. All reactions were per-
formed under a static nitrogen or argon atmosphere in flame-
dried glassware. Elemental analyses were performed by Desert
Analytics, Inc., Tucson, AZ.
to Noyori’s procedure,22 from crotonaldehyde 17 and
(16) Roush, W. R.; Harris, D. J .; Lesur, B. M. Tetrahedron Lett 1983,
24, 2227-2230.
(17) (a) Pederson, R. L.; J ohnson, J . L.; Holysz, R. P.; Ott, A. L. J .
Am. Chem. Soc. 1957, 79, 1115-1117. (b) Slomp, G., J r.; J ohnson, J .
L. J . Am. Chem. Soc. 1958, 80, 915-921.
(18) Veysoglu, T.; Mitscher, L. A.; Swayze, J . K. Synthesis 1980,
807-810.
(19) (a) Martinelli, M. J . J . Org. Chem. 1990, 55, 5065-5073. (b)
Schlosser, M.; Tuong, H. B.; Schaub, B. Tetrahedron Lett. 1985, 26,
311-314. (c) Vedejs, E.; Marth, C. F. J . Am. Chem. Soc. 1990, 112,
3905-3909. (d) Le Bigot, Y.; Hajjaji, N.; Rico, I.; Lattes, A.; Delmas,
M.; Gaset, A. Synth. Commun. 1985, 15, 495-497. (e) Chan, T. H.;
Chang, E. J . Org. Chem. 1974, 39, 3264-3268. (f) Boden, R. M.
Synthesis 1975, 784.
P r op a r gyl Eth er 4. A mixture of 300 mg of 1-phenyl-2(E)-
buten-1-ol (2.0 mmol), 69 mg of n-Bu4NHSO4 (0.2 mmol), and
2.5 g of 50% aqueous NaOH was stirred vigorously at 0 °C. To
this mixture was added 0.68 mL of propargyl bromide (80%
in toluene, 6.0 mmol), and the two-phase system was stirred
(20) Keck, G. E.; Burnett, D. A. Synthesis 1987, 52, 2958-2960.
(21) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M. Tetrahedron
1994 50, 4363-4384.
(22) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni,
N.; Hayashi, M.; Kaneko, T.; Matsuda, Y. J . Organomet. Chem. 1990,
382, 19-37.
(23) Hoard, D. W.; Moher, E. D.; Turpin, J . A. Org. Process Res. Dev.,
in press.

1462 J . Org. Chem., Vol. 64, No. 5, 1999
Liang et al.
overnight. Approximately 20 mL of water and ice was added,
and the aqueous layer was neutralized with 6 N HCl. The
product was extracted with hexanes (3 × 50 mL), and the
combined organic layer was washed with brine, dried, and
evaporated. The oily product that remained was passed
through a short silica column to give 335 mg of pure propargyl
the reaction was quenched with aqueous NH4Cl. Extraction
with Et2O, drying, evaporation of the solvent, and purification
of the residue on a silica gel column (5% EtOAc/hexane) gave
322 mg (71% yield) of (3R,4R)-4-methylhept-5(E)-en-1-yn-3-ol
10:8a,24 colorless oil; [R]D ) +32.9 (c 3.0, CHCl3); IR νmax 3405,
2119 cm-1;1H NMR (CDCl3) δ 5.61 (6-H; dq, 15.3 and 6.3), 5.38
(5-H; dd, 15.3 and 7.7), 4.13 (3-H; br s), 2.45 (1-H; d, 1.5), 2.38
(4-H; m), 2.20 (OH; br d, 3.3), 1.68 (7-H; d, 6.2), 1.09 (4-CH3;
d, 6.8); 13C NMR (CDCl3) δ 131.5 (5), 127.9 (6), 83.5 (2), 73.6
(1), 66.2 (3), 43.4 (4), 18.1 (7), 15.7 (4-Me).
1
ether (90% yield): colorless oil; IR νmax 3294, 1062 cm-1; H
NMR (CDCl3) δ 7.25-7.38 (Ph-H; m), 5.76 (3-H; dq, 15.3 and
6.4), 5.79 (2-H; dd, 15.3 and 7.4), 4.97 (1-H; d, 7.4), 4.16/4.09
(CH2CCH; d AB q, 2.2 and-15.7), 2.42 (CCH, br t, 2.2), 1.73
(4-H; d, 6.3); 13C NMR (CDCl3) δ (carbon position) 140.8 (Ph-
1), 131.1 (2), 129.1 (3), 128.3 (Ph-3/5), 127.5 (Ph-4), 126.9 (Ph-
2/6), 81.0 (1), 80.0 (CH2CCH), 73.9 (CH2CCH), 55.1 (CH2CCH),
17.6 (4).
(3R,4R)-3-[(ter t-Bu tyld ip h en ylsilyl)oxy]-4-m eth ylh ep t-
5(E)-en -1-yn e (11). To a stirred solution of (3R,4R)-4-meth-
ylhept-5(E)-en-1-yn-3-ol 10 (600 mg, 4.8 mmol) and imidazole
(823 mg, 12 mmol) in 10 mL of dry DMF was added tert-
butyldiphenylsilyl chloride (2.02 g, 7.3 mmol). After the
mixture was stirred overnight, 50 mL of 10% aqueous NaOH
was added to destroy the excess tert-butyldiphenylsilyl chlo-
ride. The product was extracted into ether, and the extract
was first washed successively with water and 0.5 N HCl and
then dried and evaporated. Purification of the residue by
chromatography on silica gel with hexane gave 1.60 g (92%
yield) of (3R,4R)-3-[(tert-butyldiphenylsilyl)oxy]-4-methylhept-
5(E)-en-1-yne 11: colorless oil; [R]D ) +21.6 (c 3.0, CHCl3);
EI MS m/z (rel intensity) 362 (1, M+), 305 (100, [M - C4H9]+),
293 (19, [M - MeHCdCHCHMe]+); HREIMS (M+) calcd for
Alcoh ol 6 a n d Keton e 7. To a solution of 30 mg of
propargyl ether 4 (0.16 mmol) in 5 mL of THF at -78 °C was
slowly added 0.22 mL of n-BuLi (0.44 mmol, 2.0 M in hexane).
The reaction was monitored by TLC. After 3 h, the tempera-
ture was raised to -20 °C and then to 0 °C over the course of
2 h. TLC indicated two products along with starting material.
Another 0.50 mL of n-BuLi (1.00 mmol, 2.0 M in hexane) was
added, and the reaction mixture was stirred for 1 h before
quenching with saturated aqueous NH4Cl. Extraction with
ether (3 × 50 mL), drying, and solvent evaporation gave a
mixture of 6 and 7. Chromatographic separation produced 5
mg of 6 (ca. 15% yield) and 12 mg of 7 (ca. 41% yield).
Compound 6: colorless oil; 1H NMR (CDCl3) δ 7.20-7.48 (Ph-
H; m), 5.81 (2-H; d, 15.8), 5.77 (3-H; dq, 15.8 and 6.5), 2.81
C
24H30OSi 362.2066, found 362.2065; IR νmax 3307, 2116, 1427
cm-1;1H NMR (CDCl3) δ 7.72/7.38 (Ph-H; m), 5.32 (6-H; m),
5.25 (5-H; dd, 16.2 and 7.3), 4.29 (3-H; dd, 5.2 and 2.0), 2.38
(4-H; m), 2.33 (1-H; d, 2.0), 1.64 (7-H; d, 5.3), 1.11 (4-Me; d,
6.9), 1.06 (CMe3); 13C NMR (CDCl3) δ 136.1/135.9/133.6 /129.7/
129.6/127.5/127.3 (Ph), 132.4 (5), 126.1 (6), 83.3 (2), 73.5 (1),
68.0 (3), 43.6 (4), 26.9 (CMe3), 19.4 (CMe3), 18.0 (7), 14.7 (4-
Me). Anal. Calcd for C24H30OSi: C, 79.50; H 8.34. Found: C,
79.16; H, 8.40.
(CH2CCH; d, 2.3), 2.04 (CCH, br t, 2.2), 1.75 (4-H; d, 6.5); 13
C
NMR (CDCl3) δ 139.6 (Ph-1), 135.8 (2), 127.8 (Ph-3/5), 127.2
(3), 125.7 (Ph-4), 125.5 (Ph-2/6), 80.4 (CH2CCH), 75.1 (1), 72.5
(CH2CCH), 33.3 (CH2CCH), 17.7 (4). Compound 7: Colorless
oil; IR νmax 3299, 1680 cm-1; 1H NMR (CDCl3) δ 7.98 (2′-H/6′-
H; dd, 8.1 and 1.6), 7.56 (4′-H; td, 7.8 and 1.6), 7.46 (3′-H/5′-
H; td, 7.8 and 1.6), 3.20 (2-H; dd, 6.5 and -16.5), 2.85 (2-H′;
dd, 7.6 and -16.5), 2.45 (3-H; m), 2.29 (CH2CCH; m), 2.04
(CCH, br t, 2.2), 1.09 (3-Me; d, 7.1); 13C NMR (CDCl3) δ 199.3
(1), 132.8 (Ph-4), 128.5 (Ph-2/6), 128.0 (Ph-3/5), 82.4 (CH2CCH),
70.0 (CH2CCH), 44.2 (2), 28.8 (3), 25.7 (CH2CCH), 19.7 (4).
(S)-tr a n s-3-P en ten -2-ol (8). A mixture of trans-3-penten-
2-ol (933 mg, 11 mmol), trifluoroethyl laurate (4.14 g, 15
mmol), and 2.00 g of porcine pancreatic lipase was stirred in
25 mL of anhydrous diethyl ether for 80 h. The PPL was
filtered off and washed with ether (3 × 20 mL). Evaporation
of the ether produced a sticky oil that was distilled in a
Kugelrohr apparatus in vacuo (20 °C water bath, 1-0.3
mmHg) to produce 383 mg (40% yield) of (S)-trans-3-penten-
2-ol, which was condensed in a trap cooled with liquid N2:
(3S,4R)-3-[(ter t-Bu tyld ip h en ylsilyl)oxy]-4-m eth ylh ep t-
5(E)-en a l (12). 2-Methylbutene (1.0 mL 2 M in THF, 2.0
mmol) was added to 1.0 mL of BH3-THF solution (1 M, 1.0
mmol) at -25 °C, and the mixture was stirred in an ice bath
for 2 h. The reaction mixture was cooled to -50 °C and a
solution of 11 (315 mg, 0.9 mmol) in 1 mL of THF was added
all at once. The cooling bath was removed, and the reaction
mixture was allowed to warm to room temperature over 1 h.
The reaction was quenched with 2.2 M aqueous KH2PO4/K2-
HPO4 (4.8 mL) and 30% H2O2 (0.8 mL) at 0 °C. One hour later,
the THF was evaporated, and the residue was extracted into
ether (3 × 40 mL). The combined ether extract was washed
with brine, dried, and evaporated. The residue was purified
on silica gel (1% EtOAc/hexane) to give 362 mg of aldehyde
12 (83% yield): colorless oil; [R]D ) +26.0 (c 0.30, CHCl3); IR
1
colorless oil; [R]D ) -7.4 (c 12.3, CHCl3); H NMR (CDCl3) δ
ν
max 1725 cm-1; 1H NMR (CDCl3) δ 9.52 (1-H; t, 2.4), 7.69/7.40
5.57 (4-H; dq, 15.3 and 6.0), 5.47 (3-H; ddd, 15.3, 6.4 and 1.2),
4.19 (2-H; 1:4:6:4:1 pent, 6.4), 2.24 (OH; br s), 1.63 (5-H; d,
6.0), 1.19 (1-H; d, 6.4); 13C NMR (CDCl3) δ 135.5 (3), 125.5 (4),
68.7 (2), 23.3 (5), 17.5 (1).
(Ph-H), 5.28 (6-H; m), 5.22 (5-H; dd, 16.2 and 6.2), 4.19 (3-H;
m), 2.42 (2-H; m), 2.29 (4-H; m), 1.60 (7-H; d, 5.4), 1.07 (CMe3),
1.02 (4-Me; d, 6.9);13C NMR (CDCl3) δ 202.0 (1), 136.1/133.6/
133.3 /130.2/129.7/127.7/127.6 (Ph), 132.3 (5), 126.2 (6), 72.8
(3), 47.6 (2), 42.2 (4), 27.1 (CMe3), 19.6 (CMe3), 18.3 (7), 14.9
(4-Me).
(3R,4R)-4-Meth ylh ep t-5(E)-en -1-yn -3-ol (10). To a vigor-
ously stirred mixture of neat (S)-trans-3-penten-2-ol 8 (628 mg,
7.3 mmol), n-Bu4NHSO4 (138 mg, 0.41 mmol), and 40%
aqueous NaOH (5 mL) was slowly added propargyl chloride
(767 mg, 10.3 mmol, 745 µL) at 0 °C. Vigorous stirring was
continued overnight, and the mixture was neutralized with
aqueous HCl at 0 °C. The product was extracted into pentane,
the solvent was dried and evaporated, and the propargyl ether
was purified on a short silica gel column (2% Et2O/pentane)
to give 778 mg (86% yield) of (S)-trans-2-(2-propynyloxy)-3-
pentene 9:8a colorless oil; [R]D ) -118.9 (c 2.0, CHCl3); IR νmax
3297 cm-1;1H NMR (CDCl3) δ 5.70 (4-H; dq, 18.5 and 6.5), 5.31
(3-H; ddd, 18.5, 7.2 and 1.4), 4.15 (CH2CCH; dd, 2.1 and -15.6),
4.01 (CH2CCH; dd, 2.1 and -15.6), 4.01 (2-H; m), 2.38 (CCH;
t, 2.1), 1.73 (5-H; dd, 6.5 and 1.4), 1.25 (1H; d, 6.3); 13C NMR
(CDCl3) δ 132.2 (3), 128.7 (4), 80.5 (CCH), 75.4 (CCH), 73.5
(2), 54.8 (CH2CCH), 21.4 (1), 17.6 (5). An aliquot of n-
butyllithium in hexane (2.5 M, 5.1 mL, 12.8 mmol) was
evaporated in vacuo and the residue cooled to -90 °C. A
solution of (S)-trans-2-(2-propynyloxy)-3-pentene 9 (454 mg,
3.66 mmol) in 10 mL of THF was slowly added. After the
mixture was allowed to warm to room temperature overnight,
Meth yl (5S,6R)-5-[(ter t-Bu tyld ip h en ylsilyl)oxy]-6-m e-
th yln on a -2(E),7(E)-d ien oa te (13). To a stirred solution of
aldehyde 12 (315 mg, 0.83 mmol) and trimethyl phosphonoac-
etate (182 mg, 1.0 mmol) in 3 mL of THF was added
tetramethylguanidine (124 µL, 1.0 mmol) at -78 °C. After 30
min, the cooling bath was removed, and the mixture was
stirred for another 4 h. The mixture was neutralized with 1 N
aqueous HCl, and the product was extracted into ether (3 ×
35 mL). Evaporation of the dried ether extract produced a
residue that was purified on silica gel (5% EtOAc/hexane) to
give 332 g of 13 (92% yield): colorless oil; [R]D ) +41.6 (c 3.0,
CHCl3); FAB MS m/z (rel intensity) 435 (10, [M - H]+), 379
(59, [M - C4H9]+), 367 (28, [M - MeHCdCHCHMe]+), 359 (40,
[M - C6H5] +); HRFABMS ([M - H]+) calcd for C27H35O3Si
(24) Alcohol 10 was volatile, and we were unable to get mass
spectrometric data using the direct probe method; therefore, complete
characterization was performed on the derived tert-butyldiphenylsilyl
ether 11.

Synthesis of Unit A of Cryptophycin
J . Org. Chem., Vol. 64, No. 5, 1999 1463
435.2355, found 435.2344; IR νmax 1729 cm-1; 1H NMR (CDCl3)
δ 7.68/7.38 (Ph-H), 6.75 (3-H; dt, 15.6 and 7.4), 5.62 (2-H; d,
15.6), 5.34 (8-H, m), 5.29 (7-H, m), 3.70 (5-H, m), 3.68 (OMe,
s), 2.28 (4-H, m), 2.20 (6-H, m), 1.62 (9-H; d, 5.3), 1.08 (CMe3),
0.99 (6-Me; d, 6.9); 13C NMR (CDCl3) δ 166.7 (1), 146.4 (3),
136.0/134.2/133.8/129.62 /129.56/127.5/127.4 (Ph), 132.5 (7),
125.8 (8), 122.6 (2), 76.2 (5), 51.3 (OCH3), 41.7 (6), 36.8 (4),
27.0 (CMe3), 19.4 (CMe3), 18.1 (9), 14.7 (6-Me). Anal. Calcd
for C27H36O3Si: C, 74.27; H, 8.31. Found: C, 74.31; H, 8.15.
Meth yl (5S,6R)-5-[(ter t-Bu tyldiph en ylsilyl)oxy]-6-m eth -
yl-8-p h en yl-octa -2(E),7(E)-d ien oa te (15). Ozone was passed
through a solution of methyl ester 13 (436 mg, 1.0 mmol) and
97 µL of pyridine in 15 mL of CH2Cl2 at -78 °C, and the
progress of the ozonolysis was monitored by TLC. After the
methyl ester had been consumed, approximately 500 mg of
zinc dust and 1 mL of glacial acetic acid were added. The
reaction was slowly warmed to 25 °C. The mixture was filtered,
and the filtrate was washed successively with saturated
aqueous CuSO4 and NaHCO3. The solvent was evaporated, and
the crude methyl (5S,6R)-5-[(tert-butyldiphenylsilyl)oxy]-6-
methyl-7-oxohept-2(E)-enoate (14) (360 mg, 85% yield) was
used in the next step with no further purification. To a stirred
solution of aldehyde 14 (360 mg, 0.85 mmol) in 15 mL of THF
at -78 °C was added 8.8 mL of a cold (-78 °C) solution of the
ylide (0.88 mmol) prepared from benzyltriphenylphosphonium
chloride (388 mg, 1.0 mmol) in 9.5 mL of THF and n-
butyllithium (0.45 mL, 2.5 M in hexane). After 15 min, the
cold bath was removed, and stirring was continued for 2 h.
The reaction was quenched with saturated aqueous NH4Cl,
and the THF was evaporated. The residue was extracted with
hexane twice and the combined extract was washed with brine,
dried, and evaporated. The residual oil, a 5:1 mixture of the E
and Z isomers, was dissolved in 10 mL of toluene containing
thiophenol (0.02 M) and VAZO 88 (0.006 M), and the mixture
was refluxed for 5 h. After the mixture was cooled to room
temperature, hexane (15 mL) was added, and the organic
solution was washed successively with 10% aqueous NaOH
and brine, dried (MgSO4), and evaporated. Chromatography
of the residue on silica gel (2% EtOAc/hexane) gave 347 mg
(82% yield) of 15: colorless oil; [R]D ) +76 (c 0.40, CHCl3);
FABMS m/z (rel intensity) 497 (5.9, [M - H]+), 441 (36, [M -
C4H9]+); HRFABMS ([M - H]+) calcd for C32H37O3Si 497.2512,
found 497.2504; IR νmax 1725, 1428 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.71/7.68 (SiPh, 2′-H, 6′-H/2′′-H, 6′′-H; d; 6.5), 7.45/
7.43 (SiPh, 4′-H/4′′-H; t; 7.4), 7.39/7.38 (SiPh, 3′-H, 5′-H/3′′-H,
5′′-H; dd; 7.4, 6.5), 7.29/7.21 (Ph-H5; m), 6.77 (3-H; dt; 15.6
and 7.5), 6.25 (8-H, d, 16.0), 6.14 (7-H, dd, 16.0 and 7.8), 5.66
(2-H, dt, 15.6 and 1.4), 3.82 (5-H, ddd, 6.8, 5.5, and 3.5), 3.68
(CO2CH3, s), 2.42 (6-H, m), 2.35 (4-H, m), 2.30 (4-H′, m), 1.12
(6-CH3, d, 7.1), 1.08 (CMe3, s); 13C NMR (125 MHz, CDCl3) δ
166.7 (1), 145.9 (3), 137.6 (9), 136.0 (SiPh, 2′, 6′/2′′, 6′′), 134.1/
133.7 (SiPh, 1′/1′′), 131.8 (8), 130.6 (7), 129.8/129.7 (SiPh, 4′/
4′′), 128.5 (11/13), 127.6/127.5 (3′, 5′/ 3′′, 5′′), 127.1 (12), 126.1
(10/14), 122.9 (2), 76.3 (5), 51.3 (OCH3), 42.2 (6), 37.2 (4), 27.1
(CMe3), 19.5 (CMe3), 16.2 (6-CH3). Anal. Calcd for C32H38O3-
Si: C, 77.06; H, 7.68. Found: C, 77.45; H, 7.36.
(S)-(E)-4-Hexen -3-ol (19). Diethylzinc (1.0 M in hexane,
2.85 L, 2.85 mol) was combined with (S)-1-piperidino-3,3-
dimethyl-2-butanol 18 (4.47 g, 24.1 mol, 68.5% ee), and the
mixture was stirred for 20 min at room temperature. The
reaction mixture was cooled to -60 °C, 200 mL (2.32 mol) of
trans-crotonaldehyde 17 was added, and the mixture was
allowed to warm to 0 °C and stir for 6 h. The reaction was
quenched by carefully adding 1.5 L of saturated aqueous NH4-
Cl and stirring the biphasic mixture for 30 min. The mixture
was filtered, the organic phase was washed with 1 M aqueous
HCl (980 mL), and the combined aqueous extract was ex-
tracted with 980 mL of hexane. The combined organic phase
was washed with 980 mL of brine, dried (MgSO4), and carefully
concentrated in vacuo. Distillation at atmospheric pressure
(135° C) produced 155.3 g (64% yield) of 19 as a colorless oil:
[R]D ) +12.4 (c 2.12, EtOH), 83% ee; IR (CHCl3) νmax 3607
1
cm-1; H NMR (CDCl3) δ 5.64 (4-H, ddq, 15.3, 6.4, 0.8), 5.45
(5-H, ddq, 15.3, 7.0, 1.5), 3.94 (3-H, ddd, 6.7, 6.7, 6.7), 1.67
(2-H, dd, 6.4, 1.5), 1.65-1.40 (6-H, m), 0.88 (1-H, t, 7.4); 13C
NMR (CDCl3) δ 134.0, 126.9, 74.5, 30.1, 17.7, 9.7; FDMS m/z
100 (M+).
Meth yl (5S,6R)-5-Hyd r oxy-6-m eth yl-8-p h en ylocta -2(E),
7(E)-d ien oa te (16). To a stirred solution of silyl ether 15 (250
mg, 0.5 mmol) in 15 mL of acetonitrile was added 5 mL of 49%
aqueous hydrofluoric acid. The clear solution was stirred
overnight, saturated aqueous NaHCO3 was slowly added to
neutralize the excess acid, and the acetonitrile was evaporated
under reduced pressure. The product was extracted with ether
(2 × 80 mL), and the organic layers were combined, dried, and
concentrated. The residue was purified by flash column
chromatography to give 242 mg of 16 (93% yield): colorless
1
oil; [R]D ) +55.2 (c 0.31, CHCl3); IR νmax 3456, 1722 cm-1; H
NMR (CDCl3) δ 7.39/7.23 (Ph-H5; m), 7.05 (3-H; dt; 15.6 and
7.4), 6.48 (8-H, d, 15.9), 6.13 (7-H, dd, 15.9 and 8.8), 5.93 (2-
H, dt, 15.6 and 1.5), 3.74 (CO2CH3, s), 3.64 (5-H, m), 2.49 (4-
H, m), 2.42 (6-H, m), 2.38 (4-H′, m), 1.15 (6-CH3, d, 6.8); 13C
NMR (CDCl3) δ 166.6 (1), 145.6 (3), 137.0 (9), 132.0 (8), 130.9
(7), 128.5 (11/13), 127.4 (12), 126.2 (10/14), 123.3 (2), 73.9 (5),
51.4 (OCH3), 43.3 (6), 37.4 (4), 16.8 (6-CH3).
Ack n ow led gm en t. This research was suported by
Grant No. 12623 from the National Cancer Institute,
Department of Health and Human Services. We thank
Professor Thomas Hemscheidt for many helpful discus-
sions. M.A.T. acknowledges a J apan Society for the
Promotion of Science Fellowship.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra, IR spectra, and mass spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O9815958