Synthesis of 1-aza-cryptophycin 1, an unstable cryptophycin. An unusual skeletal rearrangement

Article abstract of DOI:10.1016/S0040-4020(00)00255-6

A total synthesis of cryptophycin 337 (1-aza-cryptophycin 1, 2), an analogue of the potent antitumor antibiotic cryptophycin 1 (1), is described. Cryptophycin 337 was unstable and underwent an unexpected skeletal rearrangement. (R)-Mandelic acid was used as the sole source of asymmetry for the synthesis of unit A. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00255-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3339±3351
Synthesis of 1-Aza-cryptophycin 1, an Unstable Cryptophycin.
An Unusual Skeletal Rearrangement
*
Russell A. Barrow, Richard E. Moore, Lian-Hai Li and Marcus A. Tius
Department of Chemistry, University of Hawaii, 2545 The Mall, Honolulu, Hawaii 96822, USA
Received 23 February 2000; accepted 23 March 2000
AbstractÐA total synthesis of cryptophycin 337 (1-aza-cryptophycin 1, 2), an analogue of the potent antitumor antibiotic cryptophycin 1
(1), is described. Cryptophycin 337 was unstable and underwent an unexpected skeletal rearrangement. (R)-Mandelic acid was used as the
sole source of asymmetry for the synthesis of unit A. q 2000 Elsevier Science Ltd. All rights reserved.
The cryptophycins are highly potent, tumor-selective cyto-
toxins which have been isolated from the terrestrial blue-
green algae Nostoc sp. GSV 2241 and sp. ATCC 53789.2
Arenastatin A, (cryptophycin 24) which is a structurally
related cytotoxin, has been isolated from an Okinawan
sponge.3 Following the ®rst synthesis of cryptophycin 1,4
Sih5 and Leahy6 independently disclosed total syntheses,
while Kitagawa has described a synthesis of arenastatin
A.7 Other synthetic work directed toward the cryptophycin
skeleton has appeared since then.8 The importance of this
class of compounds as potential chemotherapeutic agents
against refractory cancers has provided the impetus for
this synthetic work, and has also motivated the present
research. As a part of our systematic structure±activity
exploration we required the preparation of the cryptophycin
analogue (2) in which the unit A to unit D ester link had
been substituted by an amide link. Our early work had
provided strong evidence that the `northwestern' region of
the molecule played an important role in determining the
potency of the cytotoxicity. For example, the cytotoxicities
(IC50's, KB cell line) of cryptophycin 1 and cryptophycin 3
were 0.0092 and 3.13 nM, respectively.9 Therefore struc-
tural modi®cations in this region have demanded our
attention. In this paper the preparation of cryptophycin
337 (2) and its remarkable reactivity are described (Fig. 1).
being approximately 2:1 at best. Furthermore, the chromato-
graphic mobilities of the two epoxide diastereomers are
similar enough that the separation is not trivial. This
problem has now been solved by addressing the issue of
C7±C8 stereochemistry during the preparation of unit A.
Commercially available and cheap (R)-mandelic acid 3
(Scheme 1) was an attractive starting material. Leahy had
also used 3 as the starting point for his synthesis of unit A,6
however, whereas Leahy combined the Evans chiral
auxiliary10 with a protected mandelaldehyde derivative to
control absolute stereochemistry, our goal was to use 3 as
the sole source of asymmetry for the synthesis of unit A.
Mandelic acid was ®rst converted to methyl mandelate 4 in
quantitative yield, which was transformed to the Weinreb
amide 5,11 and silylated (TBSˆtert-butyldimethylsilyl) to
produce 6. Exposure of 6 to freshly prepared ethyl-
magnesium bromide in THF led to ethyl ketone 7 in high
yield following distillation. Removal of the TBS group from
7 and subsequent Mosher analysis indicated that the
material was .95% enantiomerically pure. If the amide
displacement was attempted on the free alcohol, or if the
trimethylsilyl ether was used in place of TBS, the yield of
ketone suffered. Furthermore, if the TMS protecting group
was used, desilylation took place to a signi®cant extent, and
a mixture of protected and unprotected ketones was
obtained.
One of the dif®culties which has bedeviled each of the
published cryptophycin syntheses to date is the control of
the epoxide stereochemistry in unit A. The lability of this
functional group suggested that the styrene oxide be intro-
duced at the end of the total synthesis, however, the obvious
approach of epoxidising the styrene double bond suffers
from rather low stereoselectivity, the ratio of b:a epoxides
Aldehyde 8 was prepared in two steps from ethyl vinyl ether
according to the published procedures.12 Aldol condensa-
tion between the enolate derived from reaction of ketone 7
with LDA and aldehyde 8 proceeded in good yield to give a
ca. 10:1 ratio of syn and anti diastereoisomers. Lewis acid
catalyzed enolization with di-n-butylboryl tri¯ate and
HuÈnig's base produced the syn isomer as the exclusive
product.13 Hydrolytic removal of the diethyl acetal group
took place uneventfully in 87% yield. Selective homo-
logation of the aldehyde in the presence of the ketone was
Keywords: antitumour compounds; depsipeptides; natural products;
rearrangements.
* Corresponding author. Tel.: 1808-956-2779; fax: 1808-956-5908;
e-mail: tius@gold.chem.hawaii.edu
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00255-6

3340
R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
Figure 1.
accomplished with allyldiethylphosphonoacetate under
Masamune±Roush conditions.14 Tosylation of the free
hydroxyl group in 11 gave keto tosylate 12 in 86% yield.
Luche reduction15 of the ketone took place with high stereo-
selectivity (20:1) to furnish alcohol 13 in 96% yield. Reduc-
tion of the carbonyl group with lithium borohydride also
produced a mixture of diastereoisomers, but in a ratio of
approximately 6:1, whereas sodium triacetoxyborohydride
and tetramethylammonium triacetoxyborohydride gave
very low stereoselectivity. Displacement of the tosyloxy
group in 13 with tetramethylguanidinium azide16 furnished
the key intermediate 14 in 69% yield.
relationships were established using the methyl ester 15,
obtained by exposure of 10 to trimethylphosphonoacetate
(Scheme 2). The secondary alcohol group in 15 was
subjected to the advanced Mosher method.17 The results
of these experiments are summarized in Fig. 2, and clearly
demonstrate that the stereochemistry at C5 must be R.
Subsequent reduction of the keto group in 15 produced
the diol 16 which was converted to acetonide 17, in prepara-
tion for 13C NMR analysis (see Scheme 2) according to
Rychnovsky's method.18 The chemical shifts of the geminal
methyl carbon atoms were 29.8 and 19.6 ppm whereas the
quaternary acetal carbon atom appeared at 99.4 ppm, which
is consistent with the 1,3-syn acetonide existing in a chair
conformation. The nOe enhancements which are observed
between Hb and Hc lend further support for the 1,3-syn
It was important to determine the stereochemistry at C5,
C6 and C7 in an unambiguous way. The stereochemical
Scheme 1. (a) CH2N2, Et2O, 10 min, 08C, 100%; (b) HNCH3(OCH3)´HCl, Me3Al, PhH, 08 to 58C, 2 h; add 4; 12 h, rt, 93%; (c) TBSOTf, Et3N, CH2Cl2, 3 h,
08C, 93%; (d) EtMgBr, THF, 5 h, 94%; (e) Bu2BOTf, iPr2NEt, CH2Cl2, 2788C; 15 min; 08C, 2 h; add 8, 2788C, 1 h; 08C, 2 h; MeOH, H2O2, 08C, 2 h, 65%; (f)
Cl3CCO2H, CH2Cl2/H2O (20:1), rt, 1 h, 87%; (g) allyldiethylphosphonoacetate, LiCl, iPr2NEt, CH3CN, rt, ca. 4 h, 63%; (h) TsCl, KOH (s), THF, 08C to rt,
86%; (i) NaBH4, CeCl3´7H2O, EtOH, 08, 96%; (j) tetramethylguanidiniumazide, CH3NO2, 70±808C, 5 h, 69%.

R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
3341
Scheme 2. (a) (H3CO)2P(O)CH2CO2CH3, LiCl, iPr2NEt, CH3CN, rt, 3 h, 77%; (b) LiBH4, THF, 278 to 2308C, 70%; (c) (H3CO)2C(CH3)2, PPTS, CH2Cl2, rt,
1 h. 95%; (d) TsCl, KOH (s), THF, 08C to rt, 83%; (e) NaBH4, CeCl3´7H2O, EtOH, 08C, 2.5 h, 96%; (f) CsOAc, DMF, rt; aq HF, CH3CN, 86%.
relationship of the diol. From the known stereochemistry at
C5 it then follows that the stereochemistry at C7 is R. The
small coupling constants between Ha and Hc (Jacˆ1.5 Hz)
and between Ha and Hb (Jabˆ1.8 Hz) indicate that the C6
methyl group is axial in the acetonide ring, that the stereo-
chemistry at C6 is S, and that the aldol reaction of 7
produced 9 with syn stereochemistry.
hydroxyl or by a tosyloxy group, hydroxyketone 15 was
converted to tosylate 18 and reduced to hydroxytosylate
19 (Scheme 2). This material was not stable, and upon
standing at room temperature silyl group migration from
the benzylic (C8) position to the homobenzylic position
took place, followed by intramolecular displacement of
the tosyloxy group to form the tetrahydrofuran derivative
(20). The same transformation could also be accomplished
very easily by exposure of 19 to cesium acetate in DMF at
room temperature. Brief treatment of the product with aq HF
In order to show that the stereochemical outcome of
the reduction is the same whether C5 is substituted by a
Figure 2. Absolute stereochemical determination of 15 by the advanced Mosher method.17 The absolute stereochemistry of the secondary alcohol was shown to
be R. Chemical shifts are shown in Hertz down®eld from TMS, 0.00 Hz.

3342
R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
Scheme 3. (a) PPh3, THF, H2O, 50±608C, 12 h; (b) 22, DMF, FDPP, iPr2NEt, rt, 5 min; add 21, 4 h, rt; 74% for two steps from 14; (c) Pd(PPh3)4, THF,
morpholine, rt, 4 h, 91%; (d) FDPP, DMF; add 25, Et3N, rt, 5 h, 69%; (e) TFA, 08C to rt, 1 h; evaporate to dryness; 2-hydroxypyridine, PhMe, rt, 20 h, 50%.
in DMF gave a high yield of 20. Mosher analysis showed
that the stereochemistry at C7 in 20 was also R, and there-
fore reduction of hydroxyketone 15 or tosyloxy ketone 18
gives the syn-1,3 stereochemistry.
reduced to the corresponding amine by treatment with
triphenylphosphine (Scheme 3) to afford 21 which was
then coupled with 22, the protected C-D unit, in 74% overall
yield from 14. Removal of the allyl group of 23 took place
with palladium(0) catalysis. As the intention was to close
the macrocycle by allowing the primary amine group of
unit C to attack an activated ester group of unit B, 24
was coupled with O-methylchlorotyrosine derivative 25,4
Having secured the critical stereochemistry in unit A, atten-
tion was focussed on the assembly of unit A through D, and
the closure of the macrocycle. The azido group in 14 was
Scheme 4. (a) (i) PPTS, (MeO)3CH, CH2Cl2, rt, 2 h; (ii) MeCOBr, CH2Cl2, 6 h, rt; (iii) aq NaHCO3; DME, EtOH, MeOH, KHCO3, 408C, 15 h; (b) column
chromatography on SiO2; 62% from 27.

R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
3343
leading to seco compound 26. Macrocyclization of 26 was
accomplished in 50% yield in a single operation, without
isolating any intermediates. Exposure of 26 to TFA at 08C,
followed by warming to room temperature and evaporation
to dryness, served to cleave the Boc group and produced the
tri¯uoroacetate salt of the primary amine group of unit C.
Simply exposing this amine salt to 2-hydroxypyridine for
20 h at room temperature in toluene solution led to the
1-aza-cryptophycin 22 analogue, cryptophycin 226 (27).8e
The trichloroethyl group in unit B served to both mask the
carboxy group of 25 during the coupling step which led to
26, and also provided the carbonyl activation for the ring
closure step. This concludes a description of a brief
synthesis of cryptophycin 226 (27) (1-aza-cryptophycin 22).
the amide carbonyl oxygen atom of unit D at the benzylic
carbon atom. Loss of a proton from the amide nitrogen
completes the process, leading to the seven-membered
ring imino ether group of 28. The mechanism which has
been proposed is supported by the stereospeci®city of the
formation of 28. Alternative mechanisms involving a
discreet benzylic carbocation would have been expected
to lead to diastereomeric products, and perhaps also to
products resulting from carbocation rearrangement. For
example, treatment of cryptophycin 1 with ferric chloride
leads to the C7 ketone, presumably through the inter-
mediacy of a benzylic carbocation. No such ketone was
detected in the rearrangement of 2 to 28. An alternative
reaction pathway leading to a six-membered ring iminoester
can also be imagined, however, no evidence for this product
was detected. If the six-membered ring iminoester was
All the cryptophycin SAR work indicated that compounds
with the C7±C8 epoxide were the most potent cytotoxins.
Consequently, our goal had been to convert the syn-diol
group in 27 to the epoxide. This was accomplished through
the intermediacy of the cyclic orthoester, which was
prepared from 27 and trimethyl orthoformate. Exposure of
the orthoformate to acetyl bromide in dichloromethane led
to an intermediate formyloxy bromide which was immedi-
ately exposed to potassium bicarbonate.19 The crude product
was a mixture of two compounds, one of which appeared to
be the desired epoxide 2 (cryptophycin 337), and another,
which turned out to be 28 (cryptophycin 338; Scheme 4).
The characteristic epoxide signals could be clearly seen at
3.0 (H-7) and 3.7 (H-8) ppm in the 1H NMR spectrum of the
mixture. Approximately equal amounts of 2 and 28 were
present in the crude product mixture. The conversion of 2
to 28 took place spontaneously, even at 258C in the freezer.
The isomerization reaction also took place during our
attempts to separate the product mixture by chromato-
graphy. Flash column chromatography on basic alumina,
HPLC on cyanopropyl, or reverse phase HPLC on C18
stationary phases failed to produce pure 2, leading instead
to mixtures which were enriched in 28. Chromatography on
silica gel led to 28 as the exclusive product. We were unable
to secure a pure sample of 2, since it rearranged spon-
taneously and all of the conditions for the chromatography
evidently catalyzed its conversion to 28. As a result,
cryptophycin 337 was not considered any further as a
candidate for in vivo SAR studies.
1
present, it was below the detection limit of H NMR. The
striking difference in reactivity that substitution of oxygen
by nitrogen in unit D of the cryptophycins engenders may
re¯ect a lowering of the kinetic barrier for nucleophilic
attack at C8, this being a consequence of higher electron
density on the amide carbonyl oxygen atom as compared to
the ester. Release of strain upon cleavage of the epoxide
ring provides the thermodynamic driving force for the
rearrangement.
In conclusion, a synthesis of cryptophycin 226 has led to the
discovery of an unanticipated reaction pathway in this
series. The exceptional reactivity of the styrene oxide func-
tion in 2 precludes the consideration of this compound as a
candidate for clinical development, while underscoring the
critical role which the epoxide plays in cryptophycin SAR.
The aldol method for the control of stereochemistry in unit
A, has been demonstrated successfully. This method has
provided a practical solution to a problem which was not
addressed in a satisfactory way in our original synthesis,4
and has general utility for cryptophycin synthesis.
Experimental
1H NMR and 13C NMR spectra were recorded at 300 MHz
1H (75 MHz 13C) or 500 MHz 1H (125 MHz 13C) in
deuteriochloroform (CDCl3) with chloroform (7.26 ppm
1H, 77.00 ppm 13C) as an internal reference. Chemical shifts
are given in d; multiplicities are indicated as br (broadened),
s (singlet), t (triplet), q (quartet), sext (sextet), sept (septet),
m (multiplet); coupling constants (J) are reported in hertz
(Hz). Infrared spectra were recorded on a Perkin±Elmer IR
1430 spectrometer. Electron impact (EI) and FAB mass
spectra were performed on a VG-70SE mass spectrometer.
Mass spectral data are reported in the form of m/z. Thin
layer chromatography (TLC) was performed on EM
Reagents precoated silica gel 60 F-254 analytical plates
(0.25 mm). Flash column chromatography was performed
on Brinkmann silica gel (0.040±0.063 mm). Tetra-
hydrofuran (THF) and ether were distilled from sodium-
benzophenone ketyl, dichloromethane (CH2Cl2) from
phosphorus pentoxide and hexane from calcium hydride.
Other reagents were obtained commercially and used as
received unless otherwise speci®ed. All reactions were
performed under a static argon atmosphere in ¯ame-dried
glassware. Organic phases were dried with MgSO4 during
The structural assignment of 28 was made on the basis of
COSY, HMQC and HMBC experiments. Further evidence
to support the structural assignment came from an isotope
exchange experiment. The following isotope-induced
chemical shifts were observed when the 13C NMR spectra
were recorded in CD3OD, or a 1:1 mixture of CD3OD/
CD3OH: unit A, C1 (Dd 0.100), C7 (Dd 0.110); unit B,
C1 (Dd 0.066), C2 (Dd 0.100); unit C, C3 (Dd 0.122).
These data indicate that in 28 C7 in unit A is substituted
by a hydroxyl group, whereas the oxygen atom at C8 is not
present as a free hydroxyl. It also indicates that the nitrogen
atom at C5 of unit A lacks a hydrogen substituent. All other
spectroscopic evidence supports the structural assignment
as 28.
The mechanism for the conversion of 2 to 28 is indicated in
Scheme 4. Proton transfer to the epoxide group in 2 provides
the activation which is necessary for nucleophilic attack by

3344
R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
workup, unless otherwise speci®ed. The purity and homo-
geneity of the products on which the high resolution mass
spectral data are reported were determined on the basis of
300 MHz H NMR and multiple elution TLC analysis or
HPLC analysis.
0.4 mmHg; [a]Dˆ29.48 (cˆ6.8, CHCl3); IR (neat) 2955,
2930, 2856, 1660, 1462, 1384, 1254, 1070, 994, 873,
778 cm21; EIMS (70 eV) m/z 309 (M1, ,1), 294
(M12CH3, 5), 252 (75), 221 (87), 192 (15), 163 (21), 149
(31), 106 (10), 105 (20), 89 (42), 77 (19), 75 (41), 73 (100);
HREIMS m/z 294.1532 (M12CH3, C15H24NO3Si, D
1
1
(R)-(2)-Methyl (2-hydroxy-2-phenyl) acetate. [(R)-(2)-
Methyl mandelate] 4. Diazomethane generated by an
adaptation of the method described in Fieser and Fieser20
was used to methylate a solution of 8.0 g (53 mmol) (R)-
(2)-mandelic acid in 50 mL ether. After TLC indicated the
complete consumption of starting material, the solvent was
evaporated to produce methyl mandelate as a ¯uffy colorless
solid, 8.7 g (100% yield): mp 56±578C [lit. 55.58C21];
[a]Dˆ2140.78 (cˆ1.4, CHCl3), [a]Dˆ2143.98 (cˆ2.7,
CH3OH). IR (neat) 3390, 2954, 1740, 1434, 1211, 1067,
20.6 mmu); H NMR (300 MHz, CDCl3) d 7.43 (200/600-
H, d, 7.0), 7.25±7.35 (300/400/500-H, m), 5.59 (2-H, s), 3.49
(OCH3, bs), 3.13 (NCH3, s), 0.91 (SiCMe3, s), 0.12 (SiMe,
s), 0.04 (SiMe, s); 13C NMR (75 MHz, CDCl3) d 172.0 (2),
139.5 (100), 128.2 (300/500), 127.7 (400), 126.7 (200/600), 73.7 (1),
60.7 (OCH3), 33.2 (NCH3), 25.9 (SiCMe3), 18.4 (SiCMe3),
24.7 (SiMe), 24.9 (SiMe).
(R)-(1)-(1-tert-Butyldimethylsilyloxy-1-phenyl)butan-2-
one 7. To a stirred solution of 5.5 g (18 mmol) of Weinreb
amide 6 in 100 mL THF at 08C was added freshly prepared
ethylmagnesium bromide (1.8 M in Et2O, 30 mL, 54 mmol).
After the addition was complete (ca. 30 min, during which
time a precipitate may develop) the mixture was stirred at
08C for 5 h, after which time TLC indicated that the reaction
was complete. The mixture was diluted with 200 mL Et2O
and washed with 200 mL 10% w/w aq KHSO4 solution, then
brine. The ethereal layer was dried and concentrated to give
a pale yellow oil. Short path distillation produced 4.6 g of
the desired compound as a mobile colorless oil (94% yield):
bp 103±1058C @ 0.8 mmHg; [a]D128.08 (cˆ17.5, CHCl3);
IR (neat) 2955, 2930, 2858, 1720, 1462, 1346, 1254, 1099,
1071, 871, 837, 780 cm21; EIMS (70 eV) m/z 263
(M12CH3, 3), 221 (71), 192 (4), 163 (5), 149 (6), 115
(5), 91 (6), 75 (19), 73 (100); HREIMS m/z 263.1457
1
982, 738 cm21; H NMR (300 MHz, CDCl3) d 7.3±7.5
(Ph5, m), 5.20 (2-H, d, 5.8), 3.78 (OCH3, s), 3.48 (2-OH,
d, 5.8).
(R)-(2)-N-Methyl-N-methoxyl(2-hydroxy-2-phenyl) aceta-
mide 5. N-methyl-O-methyl hydroxylamine hydrochloride
(4.6 g, 47.4 mmol) was placed in a dry ¯ask equipped with a
stir bar and attached to a mercury bubbler. Anhydrous
benzene (50 mL) was added and the suspension cooled to
ca. 08C. Trimethylaluminum (2 M solution in hexanes,
23.7 mL, 47.4 mmol) was then added slowly [rapid genera-
tion of methane occurs] between 0±58C. The mixture was
allowed to warm to rt and was stirred for 2 h. The aluminum
amide thus prepared (ca. 0.7 M) was used immediately in
the next step.
1
(M12CH3, C15H23O2Si, D 1.0 mmu); H NMR (300 MHz,
A solution of 4.0 g (24 mmol) methyl mandelate in 30 mL
dry benzene was added with stirring to the aluminum amide
solution at rt over 20 min. The solution was stirred at rt
overnight. The reaction mixture was quenched at 08C by
the addition of dilute HCl (5% aq, 50 mL). The phases
were separated and the aqueous phase was extracted with
EtOAc. The combined organic extracts were washed with
water and brine, dried and concentrated to produce 4.35 g of
5 as a colorless waxy solid (93% yield). This material was
essentially pure and was used as obtained after workup in
the next reaction. [a]Dˆ286.78 (cˆ5.6, CHCl3); IR (neat)
CDCl3) d 7.42 (200/600-H, d, 7.3), 7.27±7.35 (300/400/500-H, m),
5.08 (1-H, s), 2.62 (3-Hb, dq, 18.6, 7.3), 2.46 (3-Ha, dq, 18.6,
7.3), 0.95 (SiCMe3, s), 0.94 (4-H3, t, 7.3), 0.08 (SiMe, s),
20.02 (SiMe, s); 13C NMR (75 MHz, CDCl3) d 210.7 (2),
139.0 (100), 128.3 (300/500), 127.8 (400), 125.9 (200/600), 81.1 (1),
29.3 (3), 25.8 (SiCMe3), 18.2 (SiCMe3), 7.5 (4), 24.9
(SiMe), 25.1 (SiMe).
(3R, 4S, 6R)-1,1-Diethoxy-3-hydroxy-4-methyl-5-oxo-6-
[(tert-butyl-dimethylsilyl)oxy]-6-phenylhexane 9. To a
stirred solution of ketone 7 (1.87 g, 6.7 mmol) in 35 mL
anhydrous CH2Cl2 was added diisopropylethylamine
(1.04 g, 1.4 mL, 8.1 mmol) followed by dibutylboron
tri¯ate22 (7.4 mL of a 1 M solution in CH2Cl2) at 2788C.
The mixture was stirred at 2788C for 15 min then warmed
to 08C and stirred for 2 h. The clear orange solution was
cooled to 2788C and 1,1-diethoxy-3-propanal 8 (1.50 g,
10.1 mmol) was added dropwise in 5 mL of anhydrous
CH2Cl2. The mixture was stirred at 2788C for 1 h then
allowed to warm to 08C and stirred for an additional 2 h at
this temperature. The mixture was cooled to 2788C, 20 mL
of sat. aq. NH4Cl was added, and the mixture stirred
vigorously while warming to rt. The reaction mixture was
diluted with 50 mL CH2Cl2, the organic layer was separated,
then mixed with MeOH/H2O2 (3:1, 20 mL) at 08C. This
mixture was allowed to warm to rt and vigorously stirred
for 2 h before the organic layer was separated, washed with
40 mL sat. aq. NaHCO3 followed by brine. The organic
layer was collected, dried and concentrated to give a pale
yellow oil that consisted of the desired product and excess
aldehyde 8. Removal of the excess aldehyde at high vacuum
3431, 2938, 1650, 1454, 1372, 1190, 1059, 989, 702 cm21
;
EIMS (70 eV) m/z 195 (M1, 1), 107 (37), 106 (37), 105
(100), 79 (23), 77 (80); HREIMS m/z 195.0922 (M1,
C10H13NO3, D 22.7 mmu); H NMR (300 MHz, CDCl3) d
1
7.3±7.5 (Ph5, m), 5.37 (2-H, bs), 4.30 (2-OH, bs), 3.23
(NCH3 and OCH3, s); 13C NMR (75 MHz, CDCl3) d
173.3 (2), 139.7 (100), 128.5 (300/500), 128.1 (400), 127.4 (200/
600), 71.5 (1), 60.6 (OCH3), 32.7 (NCH3).
(R)-(2)-N-Methyl-N-methoxyl(2-tert-butyldimethylsilyl-
oxy-2-phenyl) acetamide 6. To a solution of amide 5 (4.0 g,
20.5 mmol) at 08C in 60 mL dry CH2Cl2, was added triethyl-
amine (5.4 mL, 4.1 g, 40.6 mmol) followed by tert-butyl-
dimethylsilyltri¯uoromethanesulfonate (TBSOTf, 6.9 mL,
7.9 g, 30.0 mmol). The sample was stirred at 08C for 3 h,
diluted with 100 mL Et2O and washed with 100 mL sat. aq.
NH4Cl. The organic layer was collected, washed with water
and brine, then dried and concentrated to produce a pale
yellow oil. Short path distillation produced 5.9 g of 6 as a
colorless mobile oil (93% yield): bp 111±1148C @

R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
3345
provided a product that could be used in the following
reaction. The crude product was puri®ed by column
chromatography (silica, 15% EtOAc/hexane) to provide
1.85 g of 9 as a colorless mobile oil, (65% yield):
[a]Dˆ28.68 (cˆ1.2, CHCl3); IR (neat) 3507, 2966, 2919,
was added, and the colorless suspension became orange.
The mixture was stirred at rt for ca. 4 h until TLC (silica,
15% EtOAc/hexane) indicated consumption of starting
material, then 80 mL water was added and the suspension
stirred for 10 min. The mixture was diluted with 100 mL
Et2O, the phases separated and the organic layer washed
with water, brine, dried, and the solvent evaporated to
give a pale yellow oil. Chromatographic puri®cation (silica,
15% EtOAc/hexane) produced 1.15 g of 11 as a colorless oil
(63% yield): [a]Dˆ211.38 (cˆ4.6, CHCl3); IR (neat) 3518,
2931, 2858, 1722, 1715, 1657, 1453, 1257, 863, 837,
780 cm21; EIMS (70 eV) m/z 375 (M12OCH2CHvCH2,
,1), 357 (M12tBu±H2O, ,1), 309 (7), 263 (7), 222 (48),
221 (100), 163 (14), 149 (24), 105 (19), 91 (26), 75 (99), 73
(99); HREIMS m/z 375.2021 (M12OCH2CHvCH2,
C21H31O4Si, D 23.0 mmu), 357.1551 (M12tBu±H2O,
2872, 1713, 1448, 1255, 1120, 1061, 861, 832, 773 cm21
;
EIMS (70 eV) m/z 379 (M12OEt, ,1), 361 (M12OEt±
H2O, 1), 321 (M12OEt±tBu±H, 1), 263 (3), 249 (3), 222
(18), 221 (100), 103 (12), 75 (49), 73 (90), HREIMS m/z
379.2247 (M12OEt, C21H35O4Si, D 5.8 mmu), 361.2200
(M12OEt±H2O, C21H33O3Si, D 20.1 mmu), 321.1495
(M12OEt±tBuH, C17H25O4Si, D 2.7 mmu); 1H NMR
(500 MHz, CDCl3) d 7.40 (8/12-H, bd, 7.4), 7.33 (9/11-H,
bdd, 7.4, 2.2), 7.28 (10-H, bt, 7.2), 5.12 (6-H, s), 4.60 (1-H,
dd, 5.8, 5.3), 3.95 (3-H, ddd, 9.9, 5.2, 2.5), 3.67 (100-Hb, dq,
9.4, 7.2), 3.58 (100-Hb, dq, 9.4, 7.2), 3.47 (100-Ha, dq, 9.4,
7.2), 3.46 (100-Ha, dq, 9.4, 7.2), 3.32 (3-OH, s, W1/2ˆ10),
3.07 (4-H, dq, 5.2, 6.9), 1.62 (2-Hb, ddd, 14.1, 9.9, 5.3), 1.51
(2-Ha, ddd, 14.1, 5.8, 2.5), 1.19 (200-H3, t, 7.2), 1.16 (200-H3,
t, 7.2), 0.93 (4-Me, d, 6.9), 0.93 (SiCMe3), 0.09 (SiMe, s),
20.04 (SiMe, s); 13C NMR (125 MHz, CDCl3) d 213.7 (5),
138.4 (7), 128.5 (9/11), 128.2 (10), 126.4 (8/12), 101.8 (1),
80.7 (6), 68.4 (3), 62.3 (100), 61.6 (100), 45.1 (4), 38.3 (2),
25.8 (SiCMe3), 18.2 (SiCMe3), 15.3 (200), 15.2 (200), 12.4 (4-
Me), 24.9 (SiMe), 25.0 (SiMe).
1
C20H25O4Si, D 22.9 mmu); H NMR (500 MHz, CDCl3)
d 7.39 (10/14-H, bd, 7.2), 7.35 (11/13-H, dd, 7.2, 6.9),
7.29 (12-H, m), 6.89 (3-H, ddd, 15.6, 8.1, 7.4), 5.94
(200-H, ddt, 17.1, 10.4, 5.7), 5.88 (2-H, d, 15.6), 5.33
(300-Ht, ddt, 17.1, 1.2, 1.2), 5.24 (300-Hc, ddt, 10.4, 1.2,
1.2), 5.11 (8-H, s), 4.63 (100-H2, d, 5.7), 3.90 (5-H, m),
3.13 (6-H, dq, 3.0, 7.2), 2.91 (5-OH, s), 2.34 (4-Hb, dddd,
14.6, 8.1, 6.7, 1.5), 2.12 (4-Ha, dddd, 14.6, 7.4, 6.2, 1.1),
0.92 (SiCMe3, s), 0.90 (6-Me, d, 7.2), 0.07 (SiMe, s), 20.03
(SiMe, s); 13C NMR (125 MHz, CDCl3) d 214.6 (7), 165.7
(1), 145.2 (3), 138.1 (9), 132.3 (200), 128.6 (11/13), 128.3
(12), 126.2 (10/14), 123.4 (2), 118.2 (300), 80.6 (8), 70.0 (5),
65.0 (100), 43.3 (6), 36.7 (4), 25.7 (SiCMe3), 18.2 (SiCMe3),
10.7 (6-Me), 4.9 (SiMe), 25.1 (SiMe).
(3R, 4S, 6R)-3-Hydroxy-4-methyl-5-oxo-6-[(tert-butyl-
dimethylsilyl)oxy]-6-phenylhexanal 10. Trichloroacetic
acid (300 mg) was added to a solution of 500 mg of acetal
9 (1.18 mmol) in a mixture of 20 mL CH2Cl2 and 1 mL
water. The solution was stirred vigorously at rt for 1 h,
then diluted with 20 mL water, the phases separated, and
the organic layer washed with 20 mL sat. aq NaHCO3 and
brine. The organic layer was dried and the solvent evapo-
rated to produce 363 mg of 10 as a colorless oil (87% yield
following chromatographic puri®cation on silica, 25%
EtOAc/hexane): [a]Dˆ212.28 (cˆ1.0, CHCl3); IR (neat)
3492, 2955, 2930, 2858, 1722, 1712, 1453, 1256, 1118,
1068, 867, 837, 779 cm21; EIMS (70 eV) m/z 349
(M12H, ,1), 314 (M122H2O, 1), 293 (M12tBu, 3), 275
(M12tBu±H2O, 2), 249 (6), 222 (19), 221 (100), 163 (6),
105 (13), 75 (63), 73 (90); HREIMS m/z 314.1702
Allyl (5R, 6S, 8R)-5-tosyloxy-6-methyl-7-oxo-8-[(tert-
butyldimethylsilyl)oxy]-8-phenyl-oct-2(E)-enoate
12.
Ketoalcohol 11 (380 mg, 0.88 mmol) was dissolved in
40 mL reagent grade THF23 and cooled to 08C. Tosyl
chloride (850 mg, 4.5 mmol) was added followed by the
slow addition (®ve portions over 30 min) of freshly
powdered KOH (500 mg, 8.9 mmol). After addition was
complete the reaction mixture was warmed to rt and allowed
to stir until TLC indicated that no starting material
remained. The reaction mixture was then diluted with
100 mL Et2O and washed with 80 mL sat. aq. NaHCO3,
water and brine. The organic layer was dried and the solvent
evaporated to give a waxy solid that was puri®ed by ¯ash
chromatography (silica, 15% EtOAc/hexane). Tosylate 12
was obtained as a colorless viscous oil (442 mg 86% yield):
[a]Dˆ237.88 (cˆ4.0, CHCl3); IR (neat) 2954, 2858, 1724,
(M122H2O, C19H26O2Si,
D
0.0 mmu), 293.1191
(M12tBu, C15H21O4Si, D 1.8 mmu), 275.1135 (M12tBu±
H2O, C15H19O3Si, D 23.2 mmu); 1H NMR (500 MHz,
CDCl3) d 9.70 (1-H, dd, 1.9, 1.6), 7.40 (8/12-H, bd, 7.3),
7.35 (9/11-H, bdd, 7.3, 6.9), 7.30 (10-H, bt, 6.9), 5.14 (6-H,
s), 4.32 (3-H, ddd, 8.8, 4.4, 3.8), 3.14 (4-H, dq, 4.4, 7.1),
3.07 (3-OH, s, W1/2ˆ10), 2.48 (2-Hb, ddd, 17.0, 8.8, 1.9),
2.35 (2-Ha, ddd, 17.0, 3.8, 1.6), 0.94 (4-Me, d, 7.1), 0.93
(SiCMe3, s), 0.10 (SiMe, s), 20.02 (SiMe, s); 13C NMR
(125 MHz, CDCl3) d 213.6 (5), 201.4 (1), 138.1 (7), 128.5
(9/11), 128.4 (10), 126.3 (8/12), 80.6 (6), 67.0 (3), 47.6 (2),
44.2 (4), 25.7 (SiCMe3), 18.2 (SiCMe3), 12.0 (4-Me), 24.9
(SiMe), 25.0 (SiMe).
1658, 1454, 1365, 1258, 1177, 1097, 908, 839, 781 cm21
;
EIMS (70 eV) m/z 529 (M12tBu, 4), 357 (9), 222 (25), 221
(100), 165 (12), 105 (18), 91 (24), 73 (98); HREIMS m/z
529.1680 (M12tBu, C27H33O7SSi, D 3.6 mmu); FABMS,
nitrobenzylalcohol, m/z 609 (M1Na, 4), 587 (M1H, 10),
529 (5), 455 (4), 415 (8), 357 (10), 283 (20), 243 (15), 221
(100); 1H NMR (500 MHz, CDCl3) d 7.75 (200/600-H, d, 8.3),
7.27±7.32 (300/500/10/11/12/13/14, m), 6.58 (3-H, ddd, 15.5,
7.5, 7.0), 5.94 (20-H, ddt, 17.1, 10.6, 5.7), 5.55 (2-H, d,
15.5), 5.33 (30-Ht, bd, 17.1), 5.26 (30-Hc, bd, 10.6), 5.10
(8-H, s), 4.93 (5-H, ddd, 8.4, 5.4, 5.4), 4.60 (10-H2, d,
5.7), 3.31 (6-H, dq, 8.4, 7.2), 2.42 (400-CH3, s), 2.40
(4-Hb, m), 2.28 (4-Ha, bddd, 15.3, 7.5, 5.4), 0.94 (6-Me,
d, 7.2), 0.89 (SiCMe3, s), 0.06 (SiMe, s), 20.10 (SiMe, s);
13C NMR (125 MHz, CDCl3) d 209.3 (7), 165.1 (1) 144.9
(400), 142.0 (3), 138.2 (9), 133.8 (100), 132.2 (20), 129.8
Allyl (5R, 6S, 8R)-5-hydroxy-6-methyl-7-oxo-8-[(tert-
butyldimethylsilyl)oxy]-8-phenyl-oct-2(E)-enoate 11. To
a ¯ame dried ¯ask at rt was added 190 mg LiCl (4.5 mmol)
and 20 mL acetonitrile. To this suspension was added allyl
diethylphosphonoacetate (1.05 g, 4.4 mmol) followed by
diisopropylethylamine (500 mg, 675 mL, 3.9 mmol). After
5 min 1.28 g (3.7 mmol) of aldehyde 10 in 5 mL acetonitrile

3346
R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
(300/500), 128.6 (11/13), 128.5 (12), 127.8 (200/600), 126.7 (10/
14), 124.7 (2), 118.2 (30), 81.1 (5), 80.5 (8), 65.0 (10), 44.2
(6), 35.6 (4), 25.7 (SiCMe3), 21.6 (400-Me), 18.2 (SiCMe3),
14.2 (6-Me), 24.9 (SiMe), 25.1 (SiMe).
bd, 10.7), 4.62 (10-H2, d, 5.6), 4.48 (8-H, d, 8.6), 3.89 (7-H,
dd, 8.6, 1.1), 3.43 (5-H, ddd, 8.6, 8.4, 3.6), 2.87 (7-OH, s),
2.54 (4-Hb, dddd, 15.0, 7.1, 3.6, 1.5), 2.24 (4-Ha, ddd, 15.0,
8.6, 7.6), 1.30 (6-H, m), 0.99 (6-Me, d, 6.9), 0.87 (SiCMe3,
s), 0.03 (SiMe, s), 20.24 (SiMe, s); 13C NMR (125 MHz,
CDCl3) d 165.6 (1), 144.7 (3), 140.6 (9), 132.2 (20), 128.5
(11/13), 128.3 (12), 127.1 (10/14), 123.8 (2), 118.1 (30),
77.7 (8), 75.7 (7), 65.0 (10), 64.6 (5), 36.9 (6), 34.5 (4),
25.8 (SiCMe3), 18.1 (SiCMe3), 9.7 (6-Me), 24.5 (SiMe),
25.1 (SiMe).
Allyl (5R, 6R, 7R, 8R)-5-tosyloxy-6-methyl-7-hydroxy-8-
[(tert-butyldimethylsilyl)oxy]-8-phenyl-oct-2(E)-enoate
13. Ketotosylate 12 (900 mg, 1.54 mmol) and cerium
trichloride heptahydrate (570 mg, 1.54 mmol) were
dissolved in 50 mL ethanol and cooled to 08C. Sodium boro-
hydride (150 mg, 3.94 mmol) was added in seven portions
over 90 min between 0±58C. The mixture was allowed to
stir for 30 min, then diluted with 100 mL Et2O. Excess boro-
hydride was destroyed by washing with 20 mL 0.1N HCl,
then the mixture warmed to rt. The phases were separated
and the organic layer washed with water, brine, dried and
concentrated to give 869 mg of 13 as a viscous colorless oil
in 20:1 diastereomeric ratio (96% yield):24 [a]Dˆ240.68
(cˆ3.7, CHCl3); IR (neat) 3563, 2953, 2857, 1723, 1658,
Data for elimination product: [a]Dˆ222.68 (cˆ2.8,
CHCl3); IR (neat) 3565, 2955, 2930, 2857, 1716, 1642,
1454, 1255, 1139, 1003, 836, 778, 701 cm21; EIMS
(70 eV) m/z 359 (M12tBu, 6), 309 (4), 235 (6), 222 (19),
221 (55), 193 (10), 165 (20), 105 (13), 91 (38), 79 (17), 75
(100), 73 (78); HREIMS m/z 359.1705, (M12tBu,
1
C20H27O4Si, D 22.7 mmu); H NMR (500 MHz, CDCl3)
d 7.25±7.33 (10/11/12/13/14-H, m), 7.25 (3-H, dd, 15.5,
9.9), 6.12 (4-H, m), 6.09 (5-H, m), 5.94 (20-H, ddt, 17.3,
10.4, 5.8), 5.81 (2-H, d, 15.5), 5.33 (30-Ht, ddt, 17.3, 1.5,
1.3), 5.23 (30-Hc, ddt, 10.4, 1.3, 1.0), 4.64 (10-H2, ddd, 5.8,
1.3, 1.3), 4.54 (8-H, d, 6.1), 3.51 (7-H, dd, 6.1, 5.3), 2.75
(7-OH, bs, W1/2ˆ50), 2.23 (6-H, ddq, 6.1, 5.3, 6.9), 1.09
(6-Me, d, 6.9), 0.88 (SiCMe3, s), 0.02 (SiMe, s), 20.26
(SiMe, s); 13C NMR (125 MHz, CDCl3) d 166.7 (1),
147.0 (5), 145.2 (3), 141.5 (9), 132.4 (20), 128.3 (11/13),
128.0 (12), 127.9 (4), 126.9 (10/14), 119.5 (2), 117.9 (30),
78.9 (7), 76.4 (8), 64.9 (10), 38.9 (6), 25.8 (SiCMe3), 18.1
(SiCMe3), 14.3 (6-Me), 24.4 (SiMe), 25.1 (SiMe).
1462, 1365, 1258, 1176, 1096, 901, 837, 779, 677 cm21
;
EIMS (70 eV) m/z 531 (M12tBu, 2), 359 (14), 309 (20),
222 (34), 221 (89), 165 (22), 105 (36), 91 (72), 73 (100);
HREIMS m/z 531.1879 (M12tBu, C27H35O7SSi,
D
1
20.6 mmu); H nmr (500 MHz, CDCl3) d 7.67 (200/600-H,
d, 8.1), 7.23±7.35 (300/500/11/12/13-H, m), 7.20 (10/14-H,
bd, 6.5), 6.56 (3-H, ddd, 15.6, 8.3, 7.6), 5.92 (20-H, ddt,
17.0, 10.8, 5.4), 5.67 (2-H, d, 15.6), 5.31 (30-Ht, bd, 17.0),
5.25 (30-Hc, bd, 10.8), 4.61 (5-H, m), 4.57 (10-H2, d, 5.4),
4.45 (8-H, d, 8.1), 3.68 (7-H, bd, 8.1) 2.75 (7-OH, s), 2.58
(4-H2, bm, W1/2ˆ25), 2.41 (400-CH3, s), 1.52 (6-H, bdq, 7.0,
6.7), 0.89 (6-Me, d, 6.7), 0.85 (SiCMe3, s), 0.00 (SiMe, s),
20.28 (SiMe, s); 13C NMR (125 MHz, CDCl3) d 165.1 (1),
144.6 (400), 142.6 (3), 140.2 (9), 134.0 (100), 132.3 (20), 129.7
(300/500), 128.5 (11/13), 128.2 (12), 127.7 (200/600), 127.0 (10/
14), 124.4 (2), 118.1 (30), 84.0 (5), 77.4 (8), 74.6 (7), 64.9
(10), 36.2 (6), 34.2 (4), 25.7 (SiCMe3), 21.6 (400-Me), 18.1
(SiCMe3), 9.5 (6-Me), 24.5 (SiMe), 25.1 (SiMe).
Methyl (5R, 6S, 8R)-5-hydroxy-6-methyl-7-oxo-8-[(tert-
butyldimethylsilyl)oxy]-8-phenyl-oct-2(E)-enoate 15. To
a ¯ame dried ¯ask at rt was added 17 mg (0.41 mmol) LiCl
and 5 mL acetonitrile followed by 75 mg trimethyl
phosphonoacetate (67 mL, 0.41 mmol) and 44 mg diiso-
propylethylamine (60 mL, 0.34 mmol). The reaction
mixture was stirred for 5 min and 120 mg of aldehyde 10
(0.34 mmol) in 1 mL of acetonitrile was added, whereupon
the colorless suspension became orange. The mixture was
stirred at rt until TLC (silica, 20% EtOAc/hexane) indicated
consumption of starting material (ca. 3 h), then 20 mL water
was added and the suspension stirred for 10 min. The
mixture was diluted with 20 mL Et2O, the phases separated
and the organic layer washed with water, brine, dried and
the solvent evaporated to give a pale yellow oil. Chromato-
graphic puri®cation (silica, 20% EtOAc/hexane) gave
108 mg of 15 as a colorless oil (77% yield): [a]Dˆ211.78
(cˆ6.1, CHCl3); IR (neat) 3500, 2953, 2930, 2857, 1725,
1715, 1660, 1454, 1257, 1097, 863, 838, 780 cm21; EIMS
(70 eV) m/z 349 (M12tBu, 1), 263 (3), 222 (13), 221 (79),
163 (6), 105 (5), 86 (36), 84 (57), 75 (26), 73 (100);
Allyl (5S, 6S, 7R, 8R)-5-azido-6-methyl-7-hydroxy-8-
[(tert-butyldimethylsilyl)oxy]-8-phenyloct-2(E)-enoate
14. A solution of hydroxytosylate 13 (870 mg, 1.48 mmol)
in 70 mL anhydrous nitromethane was stirred at 70±808C
while 490 mg (3.10 mmol) tetramethylguanidinium azide
was added. The mixture was stirred for 5 h, cooled to rt,
diluted with 100 mL Et2O and the suspension was treated
with 30 mL 0.5 N HCl. The phases were separated and the
organic phase was washed with water, then brine, dried and
concentrated to produce a pale yellow oil that was puri®ed
by ¯ash chromatography (silica, hexane to 5% EtOAc/
hexane) to yield 466 mg of 14 as a colorless mobile oil
(69% yield) and 97 mg of the conjugated diene resulting
from elimination of the tosylate as a colorless oil (16%
yield).
HREIMS m/z 349.1469 (M12tBu, C18H25O5Si,
D
1
0.2 mmu); H NMR (500 MHz, CDCl3) d 7.39 (10/14-H,
bd, 7.3), 7.34 (11/13-H, bdd, 7.3, 7.0), 7.29 (12-H, tt, 7.0,
1.3), 6.86 (3-H, ddd, 15.6, 7.8, 7.0), 5.85 (2-H, ddd, 15.6,
1.5, 1.5), 5.11 (8-H, s), 3.89 (5-H, ddd, 8.3, 5.5, 3.0), 3.72
(OCH3, s), 3.13 (6-H, dq, 3.0, 7.3), 2.93 (5-OH, s, W1/2ˆ15),
2.33 (4-Hb, dddd, 14.6, 8.3, 7.0, 1.5), 2.18 (4-Ha, dddd, 14.6,
7.8, 5.5, 1.5), 0.92 (SiCMe3, s), 0.90 (6-Me, d, 7.3), 0.07
(SiMe, s), 20.04 (SiMe, s); 13C NMR (125 MHz, CDCl3) d
214.6 (7), 166.5 (1), 145.0 (3), 138.1 (9), 128.6 (11/13),
128.3 (12), 126.2 (10/14), 123.3 (2), 80.7 (8), 70.0 (5),
Data for 14: [a]Dˆ231.18 (cˆ6.3, CHCl3); IR (neat) 3574,
2954, 2857, 2100, 1723, 1658, 1453, 1256, 1169, 1080, 836,
779, 702 cm21; EIMS (70 eV) m/z 374 (M12tBu±N2, 1),
309 (6), 222 (13), 221 (46), 193 (31), 105 (11), 91 (23), 77
(17), 75 (100), 73 (73); HREIMS m/z 374.1765 (M12tBu±
N2, C20H28NO4Si, D 2.2 mmu); 1H NMR (500 MHz, CDCl3)
d 7.27±7.35 (11/12/13-H, m), 7.25 (10/14-H, dd, 6.6, 1.5),
6.85 (3-H, ddd, 15.6, 7.6, 7.1), 5.93 (20-H, ddt, 17.1, 10.7,
5.6), 5.86 (2-H, d, 15.6), 5.31 (30-Ht, bd, 17.1), 5.23 (30-Hc,

R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
3347
51.4 (OCH3), 43.3 (6), 36.7 (4), 25.7 (SiCMe3), 18.2
(SiCMe3), 10.8 (6-Me), 24.9 (SiMe), 25.1 (SiMe).
mixture was stirred for 1 h then the solvent was evaporated
and the residue puri®ed (Sep-Pak, gradient elution, hexane
to CH2Cl2) to give 10 mg of the desired acetonide 17 as a
colorless oil (95% yield): [a]Dˆ236.88 (cˆ1.3, CHCl3); IR
(neat) 2956, 2930, 2856, 1727, 1659, 1436, 1254, 1200,
(S)-MTPA ester of 15. To a solution of 5 mg (0.01 mmol)
of 15 in 1 mL CH2Cl2 was added 40 mL triethylamine, 1 mg
DMAP and 10 mL (R)-methoxy-tri¯uoromethyl-phenyl-
acetyl chloride and the mixture was stirred for 1 h. The
reaction was diluted with 10 mL Et2O and washed with
10 mL aq. (10% w/w) KHSO4 and brine. The ethereal
layer was dried and evaporated to produce the (S)-MTPA
ester as a viscous, colorless oil as a single diastereomer:
[a]Dˆ219.08 (cˆ0.6, CHCl3); 1H NMR (300 MHz,
CDCl3) d 7.3±7.5 (2£Ph5, m), 6.71 (3-H, ddd, 15.6, 7.8,
7.3), 5.74 (2-H, d, 15.6), 5.58 (5-H, ddd, 6.3, 6.3, 5.6),
5.15 (8-H, s), 3.72 (ester-OCH3, s), 3.50 (MTPA-OCH3,
s), 3.31 (6-H, dq, 6.3, 7.1), 2.44 (4-H2, m), 0.92 (SiCMe3,
s), 0.83 (6-Me, d, 7.1), 0.09 (SiMe, s), 20.07 (SiMe, s).
1
1093, 836, 778, 701 cm21; H NMR (500 MHz, CDCl3) d
7.3±7.4 (10/11/12/13/14-H, m), 6.83 (3-H, ddd, 15.7, 7.6,
6.4), 5.80 (2-H, ddd, 15.7, 1.8, 1.3), 4.52 (8-H, d, 8.4), 3.89
(7-H, dd, 8.4, 1.5), 3.83 (5-H, ddd, 8.9, 4.6, 1.8), 3.69 (s,
OCH3), 2.33 (4-Hb, dddd, 15.0, 8.9, 6.4, 1.8), 2.02 (4-Ha,
dddd, 15.0, 7.6, 4.4, 1.3), 1.45 (10-CH3ax, s), 1.43 (10-CH3eq
,
s), 0.87 (6-Me/6-H, m), 0.80 (SiCMe3, s), 0.04 (SiMe, s),
20.09 (SiMe, s); 13C NMR (125 MHz, CDCl3) d 166.8 (1),
145.7 (3), 140.9 (9), 128.2 (11/13), 127.7 (12), 127.3 (10/
14), 122.5 (2), 99.4 (100), 78.6/75.9/72.5 (5/7/8), 51.4
(OCH3), 35.7 (6), 32.3 (4), 29.8 (10-Meeq), 25.6 (SiCMe3,
s), 19.6 (10Meax), 5.5 (6-Me), 24.5 (SiMe), 25.0 (SiMe).
(R)-MTPA ester of 15. The procedure described above was
repeated on the same scale with (S)-methoxytri¯uoro-
methyl-phenylacetyl chloride to produce the (R)-MTPA
ester as a viscous, colorless oil as a single diastereomer:
Methyl (5R, 6S, 8R)-5-tosyloxy-6-methyl-7-oxo-8-[(tert-
butyldimethylsilyl)oxy]-8-phenyl-oct-2(E)-enoate 18. A
solution of 500 mg (1.2 mmol) of 15 in 40 mL reagent
grade THF23 was cooled to 08C. Tosyl chloride (2.3 g,
12.1 mmol) was added, followed by the slow addition
(®ve portions over 30 min) of freshly powdered KOH
(340 mg, 6 mmol). After addition was complete the reaction
mixture was warmed to rt and allowed to stir until TLC
indicated that no starting material remained. The reaction
mixture was then diluted with 100 mL Et2O and washed
with 80 mL sat. aq NaHCO3, water and brine. The organic
layer was dried and evaporated to give a waxy solid that was
puri®ed by ¯ash chromatography (silica, 15% EtOAc/
hexane). Tosylate 18 was obtained as a colorless viscous
oil (575 mg, 83% yield): [a]Dˆ224.78 (cˆ2.3, CHCl3);
IR (neat) 2953, 2857, 1725, 1660, 1454, 1364, 1258,
1176, 1097, 905, 838, 780 cm21; EIMS (70 eV) m/z 388
(M12TsOH, 1), 331 (15), 222 (52), 221 (100), 155 (23),
105 (29), 91 (78), 73 (98) HREIMS m/z 221.1332 (benzylic
cleavage, C13H21OSi, D 3.0 mmu); FABMS, magic bullet
matrix plus potassium, m/z 599 (M1K, 70), 561 (M1H,
9), 503 (3), 429 (18), 389 (18), 331 (27), 257 (60), 221
1
[a]Dˆ17.88 (cˆ1.1, CHCl3); H NMR (300 MHz, CDCl3)
d 7.3±7.5 (2£Ph5, m), 6.64 (3-H ddd, 15.6, 7.8, 7.3), 5.68
(2-H, d, 15.6), 5.57 (5-H, ddd, 6.1, 5.9, 5.4), 5.12 (8-H, s),
3.71 (ester±OCH3, s), 3.49 (MTPA±OCH3, s), 3.34 (6-H,
m), 2.40 (4-H2, m), 0.94 (SiCMe3, s), 0.93 (6-Me, obsc.),
0.10 (SiMe, s), 20.06 (SiMe, s).
Methyl (5R, 6S, 7R, 8R)-5,7-dihydroxy-6-methyl-8-[(tert-
butyldimethylsilyl)oxy]-8-phenyloct-2(E)-enoate 16. A
solution of 30 mg (0.07 mmol) of ketone 15 in 3 mL THF
was cooled to 2788C and LiBH4 (15 mg, 0.68 mmol) was
added. The solution was warmed to 2308C and was stirred
for 30 min at this temperature. The solution was diluted with
10 mL Et2O, 2 mL 0.5 M HCl was added and the mixture
was warmed to rt. The organic phase was separated, washed
with water, brine, dried and evaporated to a colorless oil.
The major product was puri®ed by HPLC (10m silica,
250£10 mm, 20% EtOAc/hexane, 3 mL min21
,
Rtˆ
1
21 min) to give 21 mg of 16 as a colorless oil (70%
yield): [a]Dˆ229.38 (cˆ2.9, CHCl3); IR (neat) 3502,
2953, 2930, 2857, 1724, 1655, 1436, 1257, 1081, 837,
778, 702 cm21; EIMS (70 eV) m/z 333 (M12tBu±H2O,
,1), 309 (M12C5H7O2, 6), 222 (15), 221 (41), 193 (26),
105 (14), 91 (22), 75 (100); HREIMS m/z 333.1537
(M12tBu±H2O, C18H25O4Si, D 21.5 mmu), 309.1858
(100); H NMR (500 MHz, CDCl3) d 7.75 (20/60-H, d,
8.1), 7.25±7.35 (30/50/10/11/12/13/14-H, m), 6.54 (3-H,
ddd, 15.7, 7.9, 7.0), 5.52 (2-H, d, 15.7), 5.10 (8-H, s), 4.92
(5-H, ddd, 8.6, 5.2, 5.0), 3.70 (OCH3, s), 3.31 (6-H, dq, 8.6,
7.3), 2.42 (40-CH3, s), 2.39 (4-Hb, dddd, 15.3, 7.0, 5.0, 1.6),
2.27 (4-Ha, dddd, 15.3, 7.9, 5.2, 1.0), 0.93 (6-Me, d, 7.3),
0.89 (SiCMe3, s), 0.06 (SiMe, s), 20.10 (SiMe, s); 13C NMR
(125 MHz, CDCl3) d 209.3 (7), 165.9 (1), 144.9 (40), 141.8
(3), 138.2 (9), 133.8 (10), 129.8 (30/50), 128.6 (11/13), 128.4
(12), 127.8 (20/60), 126.7 (10/14), 124.6 (2), 81.2 (5), 80.5 (8),
51.4 (OCH3), 44.2 (6), 35.6 (4), 25.7 (SiCMe3), 21.6 (40-Me),
18.2 (SiCMe3), 14.3 (6-Me), 24.9 (SiMe), 25.1 (SiMe).
(M12C5H7O2, C17H29O3Si,
D
2.8 mmu); 1H NMR
(500 MHz, CDCl3) d 7.25±7.34 (10/11/12/13/14-H, m),
6.86 (3-H, ddd, 15.6, 7.3, 7.3), 5.85 (2-H, d, 15.6), 4.50
(8-H, d, 8.9), 3.82 (5-H, ddd, 8.6, 4.4, 2.1), 3.80 (7-H, bd,
8.9), 3.68 (OCH3, s), 3.38 (OH, s), 3.16 (OH, s), 2.36 (4-Hb,
dddd, 14.6, 8.6, 7.3, 1.5), 2.09 (4-Ha, dddd, 14.6, 7.3, 4.4,
1.5), 1.76 (6-H, m), 1.00 (6-Me, d, 7.0), 0.87 (SiCMe3, s),
0.02 (SiMe, s), 20.25 (SiMe, s); 13C NMR (125 MHz,
CDCl3) d 166.7 (1), 146.2 (3), 140.6 (9), 128.5 (11/13),
128.2 (12), 127.0 (10/14), 122.6 (2), 81.2 (7), 77.0 (8),
75.1 (5), 51.3 (OMe), 37.4 (4), 36.6 (6), 25.8 (SiCMe3),
18.1 (SiCMe3), 5.5 (6-Me), 24.5 (SiMe), 25.1 (SiMe).
Methyl (5R, 6R, 7R, 8R)-5-tosyloxy-6-methyl-7-hydroxy-
8-[(tert-butyldimethylsilyl)oxy]-8-phenyloct-2(E)-enoate
19. Ketotosylate 18 (400 mg, 0.71 mmol) and cerium
trichloride heptahydrate (265 mg, 0.71 mmol) were
dissolved in 25 mL EtOH and cooled to 08C. Sodium boro-
hydride (120 mg, 3.2 mmol) was added in 10 portions over
2 h, and the mixture was stirred for 30 min. The reaction
was diluted with 100 mL Et2O, the excess borohydride
destroyed by washing with 20 mL 0.1 N HCl, and the
mixture warmed to rt. The organic layer was collected,
Acetonide 17. To a solution of 10 mg (0.025 mmol) of 16 in
2 mL CH2Cl2 at rt was added 2,2-dimethoxy propane
(42 mg, 50 mL, 0.40 mmol) and PPTS (ca. 1 mg). The

3348
R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
washed with water and brine, dried and concentrated to
produce 385 mg of 19 as a viscous colorless oil (ca. 20:1
ratio of diastereoisomers, 96% yield):25 [a]Dˆ236.88
(cˆ3.8, CHCl3); IR (neat) 3566, 2953, 2857, 1728, 1661,
1456, 1363, 1258, 1176, 1080, 900, 837, 780 cm21; EIMS
(70 eV) m/z 505 (M12tBu, 1), 487 (M12tBu±H2O, 1), 333
(8), 273 (7), 222 (30), 221 (61), 169 (59), 137 (26), 105 (22),
91 (53), 73 (100); HREIMS m/z 505.1819 (M12tBu,
C25H33O7SSi, D 210.3 mmu), 505.1819 (M12tBu±H2O,
[a]Dˆ226.58 (cˆ1.5, CHCl3); 1H NMR (300 MHz,
CDCl3) d 7.20±7.34 (Ph5/Ph3 m), 7.06 (Ph2, bd, 7.8), 6.93
(3-H, ddd, 15.6, 7.6, 7.3), 5.85 (2-H, bd, 15.6), 5.22 (7-H,
dd, 4.4, 2.4), 5.11 (8-H, d, 4.4), 3.73 (OCH3, s), 3.70 (5-H,
obs. m), 3.02 (MTPA-OCH3, s), 2.36 (4-H2, bm), 2.01 (6-H,
m), 1.22 (6-Me, d, 7.3).
Allyl ester A-D-C-Boc Unit 23. Azide 14 (127 mg,
0.28 mmol) was dissolved in a mixture of 5 mL THF and
1 mL water. Triphenylphosphine (75 mg, 0.29 mmol) was
added in a single portion and the solution was stirred at 50±
608C for 12 h. After this time TLC (EtOAc) shows a spot
which stains with ninhydrin which is the desired amine.
Alternatively, the reaction can be monitored by the dis-
appearance of azide 14 (tlc, 20% EtOAc/hexanes). The
THF was evaporated, replaced with an equal volume of
CH2Cl2 and the phases separated. The CH2Cl2 was
evaporated to produce a mixture of crude amine 21 and
triphenylphosphine oxide as a colorless oil. The crude
material was used for the next reaction.26
1
C25H31O6SSi, D 20.9 mmu); H NMR (500 MHz, CDCl3)
d 7.67 (20/60-H, d, 8.4), 7.24±7.31 (30/50/11/12/13-H, m),
7.20 (10/14-H, bd, 7.3), 6.52 (3-H, ddd, 15.6, 8.4, 6.7), 5.64
(2-H, d, 15.6), 4.61 (5-H, ddd, 7.8, 4.7, 4.7), 4.45 (8-H, d,
8.1), 3.68 (7-H, bd, 8.1), 3.67 (OCH3, s), 2.74 (7-OH, s),
2.57 (4-H2, bm, W1/2ˆ25), 2.42 (40-CH3, s), 1.52 (6-H, m),
0.89 (6-Me, d, 6.8), 0.85 (SiCMe3, s), 0.00 (SiMe, s), 20.27
(SiMe, s); 13C NMR (125 MHz, CDCl3) d 165.9 (1), 144.6
(40), 142.4 (3), 140.3 (9), 134.0 (10), 129.7 (30/50), 128.4 (11/
13), 128.2 (12), 127.7 (20/60), 127.0 (10/14), 124.3 (2), 84.1
(5), 77.4 (8), 74.6 (7), 51.3 (OCH3), 36.2 (6), 34.1 (4), 25.7
(SiCMe3), 21.6 (40-Me), 18.1 (SiCMe3), 9.5 (6-Me), 24.5
(SiMe), 25.1 (SiMe).
Carboxylic acid 22 (120 mg, 0.38 mmol) was dissolved in
10 mL dry DMF and FDPP (130 mg, 0.34 mmol) was added
followed by diisopropylethylamine (75 mg, 100 mL,
0.58 mmol). The mixture was stirred at rt for 5 min, then
crude amine 21 (120 mg, 0.28 mmol) from the preceding
reaction in 1 mL dry DMF was added dropwise over
5 min. After 4 h the reaction was diluted with 80 mL Et2O
and washed with 20 mL 0.5 M HCl, water and brine. The
organic layer was dried and concentrated to give a pale
yellow oil. Flash chromatography (silica, 25% EtOAc/
hexane) produced 149 mg of 23 as a viscous colorless oil
(74% yield from 14): [a]Dˆ248.78 (cˆ1.6, CHCl3); IR
(neat) 3381, 2957, 2858, 1740, 1722, 1525, 1462, 1366,
1253, 1171, 1125, 1075, 868, 837, 779, 702 cm21; EIMS
(70 eV) m/z 732 (M1, ,1), 575 (16), 411 (41), 309 (8), 257
(12), 221 (47), 193 (17), 154 (28), 130 (13), 105 (15), 91
(24), 77 (20), 75 (100); HREIMS m/z 732.4364 (M1,
Methyl (2E)-4-((2S, 3R, 4R, 5R)-4-hydroxy-3-methyl-5-
phenyloxolan-2-yl)-but-2-enoate 20. Treatment of a solu-
tion of hydroxytosylate 19 in DMF with excess cesium
acetate led to the TBS ether of 20 in 86% isolated yield.
Treatment of this material at rt with aq HF in acetonitrile
gave 20 as a viscous colorless oil: [a]Dˆ228.48 (cˆ4.4,
CHCl3); EIMS (70 eV) m/z 276 (M1, 2), 274 (2), 260 (4),
258 (6), 177 (M12C5H7O2, 38), 159 (11), 140 (12), 119
(53), 100 (88), 91 (100), 77 (31); HREIMS m/z 276.1367
(M1, C16H20O4, D 20.6 mmu), 177.0920 (M12C5H7O2,
1
C11H13O2, D 20.4 mmu); H NMR (500 MHz CDCl3) d
7.30±7.40 (10/11/12/13/14-H, m), 7.09 (3-H, ddd, 15.6,
7.4, 7.2), 5.99 (2-H, ddd, 15.6, 1.5, 1.5), 4.98 (8-H, d,
4.5), 3.98 (7-H, bdd, 4.5, 2.7), 3.74 (OCH3, s), 3.71 (5-H,
ddd, 7.2, 6.9, 5.5), 2.71 (4-Hb, dddd, 14.6, 7.4, 7.2, 1.5), 2.65
(4-Ha, dddd, 14.6, 7.2, 5.5, 1.5), 2.06 (6-H, ddq, 6.9, 2.7,
7.2), 1.17 (6-Me, d, 7.2); 13C NMR (125 MHz, CDCl3) d
166.9 (1), 145.4 (3), 136.4 (9), 128.6 (11/13), 128.0 (12),
126.9 (10/14), 123.2 (2), 83.7 (5), 83.3 (8), 80.6 (7), 51.4
(OCH3), 46.9 (6), 37.8 (4), 16.7 (6-Me).
1
C39H64N2O9Si, D 1.7 mmu); H NMR (500 MHz, CDCl3)
d Unit A 7.44 (5-NH, d, 8.1), 7.21±7.29 (11/12/13-H, m),
7.20 (10/14-H, d, 6.8), 6.52 (3-H, ddd, 15.4, 8.8, 6.1), 5.90
(CH2CHvCH2, ddt, 17.2, 10.6, 5.8), 5.54 (2-H, d, 15.4),
5.29 (CH2CHvCHcHt, bd, 17.2), 5.22 (CH2CHvCHcHt,
bd, 10.6), 4.54 (CH2CHvCH2, d, 5.8), 4.43 (8-H, d, 8.8),
3.92 (5-H, m), 3.88 (7-H, bd, 8.8), 3.19 (7-OH s), 2.48
(4-Hb, dddd, 14.1, 6.1, 6.1, 1.3), 2.16 (4-Ha, ddd, 14.1,
8.8, 8.8), 1.31 (6-H, m), 0.93 (6-Me, d, 7.3), 0.86
(SiCMe3, s), 20.03 (SiMe, s), 20.25 (SiMe, s), Unit C
5.10 (3-NH, m), 3.36 (3-Hb, m), 3.20 (3-Ha, m), 2.83
(2-H, m), 1.42 (NHCO2CMe3, s), 1.21 (2-Me, d, 7.3), Unit
D 5.14 (2-H, dd, 8.6, 3.5), 1.67 (3-H2/4-H, bm), 0.91 (5-H3/
4-Me, m); 13C NMR (125 MHz, CDCl3) d Unit A 165.3 (1),
144.4 (3), 140.0 (9), 132.3 (CH2CHvCH2), 128.5 (11/13),
128.4 (12), 126.8 (10/14), 123.2 (2), 118.0 (CH2CHvCH2),
77.2 (8), 75.3 (7), 64.8 (CH2CHvCH2), 52.6 (5), 35.8 (4),
32.3 (6), 25.7 (SiCMe3), 18.1 (SiCMe3), 11.3 (6-Me), 24.5
(S)-Mosher ester of 20. To a solution of 3 mg (0.01 mmol)
of 20 in 1 mL CH2Cl2 was added triethylamine (30 mL),
DMAP (1 mg) and (R)-methoxy-tri¯uoromethyl-phenyl-
acetyl chloride (10 mL) and the mixture stirred for 1 h.
The reaction was diluted with 10 mL Et2O and washed
with 10 mL aq. (5% w/w) KHSO4 and brine. The ethereal
layer was collected, dried and concentrated to produce the
(S)-MTPA ester as a viscous, colorless oil as a single
diastereomer: [a]Dˆ229.08 (cˆ1.9, CHCl3); 1H NMR
(300 MHz, CDCl3) d 7.16±7.36 (2£Ph5, m), 7.04 (3-H,
ddd, 15.6, 7.3, 7.1), 5.96 (2-H, ddd, 15.6, 1.5, 1.5), 5.32
(7-H, dd, 4.6, 2.9), 5.10 (8-H, d, 4.6), 3.75 (5-H, obs. m),
3.73 (OCH3, s), 3.03 (MTPA±OCH3, s), 2.62 (4-H2, m),
2.19 (6-H, ddq, 6.8, 2.9, 7.1), 1.27 (6-Me, d, 7.1).
(SiMe), 25.2 (SiMe), Unit
C
174.3 (1), 155.9
(NHCO2CMe3), 79.3 (NHCO2CMe3), 43.3 (3), 40.2 (2),
28.3 (NHCO2CMe3), 14.3 (2-Me), Unit D 170.3 (1), 73.0
(2), 41.1 (3), 24.6 (4), 23.1 (4-Me), 21.6 (5).
(R)-Mosher ester of 20. The procedure described above
was repeated on the same scale with (S)-methoxy-tri¯uoro-
methyl-phenylacetyl chloride to produce the (R)-MTPA
ester as a viscous, colorless oil as a single diastereomer:
Acid A-D-C-Boc Unit 24. To a solution of 168 mg
(0.23 mmol) of allyl ester 23 in THF27 was added

R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
3349
tetrakistriphenylphosphine palladium (26 mg, 0.02 mmol).
The mixture was stirred at rt and morpholine (200 mg,
200 mL, 2.3 mmol) added dropwise over 10 min. After 4 h
the reaction was diluted with 60 mL Et2O and washed with
50 mL 0.5N HCl. The organic phase was washed with water,
brine, dried and concentrated to give a pale yellow oil. Flash
chromatography (silica, 10% EtOAc/hexane to 50% EtOAc/
hexane) produced 145 mg of acid 24 as a viscous, colorless
oil (91% yield): [a]Dˆ268.68 (cˆ2.8, CHCl3); IR (neat)
3372, 2957, 2857, 2400±3400 (br), 1715, 1704, 1660,
1529, 1462, 1367, 1252, 1173, 1125, 1075, 868, 837, 756,
702 cm21; FABMS (thioglycerol matrix1potassium) m/z
(4-Me, d, 5.8); 13C NMR (125 MHz, CDCl3) d Unit A
165.2 (1), 140.7 (3), 140.3 (9), 128.6 (11/13), 128.4 (12),
127.1 (10/14), 125.2 (2), 77.1 (8), 75.4 (7), 53.0 (5), 35.6
(4), 32.7 (6), 25.7 (SiCMe3), 18.1 (SiCMe3), 11.4 (6-Me),
24.5 (SiMe), 25.2 (SiMe), Unit B 170.0 (1), 154.2 (7),
131.1 (5), 128.7 (4), 128.5 (9), 122.5 (6), 112.3 (8), 94.2
(CH2CCl3), 74.7 (CH2CCl3), 56.1 (7-OCH3), 53.2 (2), 36.6
(3), Unit C 174.4 (1), 156.0 (NHCO2CMe3), 79.3
(NHCO2CMe3), 43.4 (3), 40.2 (2), 28.4 (NHCO2CMe3),
14.3 (2-Me), Unit D 170.5 (1), 73.0 (2), 41.0 (3), 24.6 (4),
23.2 (4-Me), 21.6 (5).
1
731 (M1K1, 80), 693 (M1H1, 15), 593 (100); H NMR
Cryptophycin 226 (27). Fully protected seco compound 26
(19 mg, 0.018 mmol) was cooled to 08C, 1 mL tri¯uoro-
acetic acid was added, and the solution stirred for 1 h. The
solvent was removed in vacuo to produce a colorless foam
which was dissolved in 20 mL EtOAc and washed with
10 mL aq. (10% w/w) Na2CO3. The phases were separated
and the organic phase was washed with 15 mL water and
15 mL brine, dried and evaporated to give the free amine as
a colorless oil. This oil (12 mg, 0.015 mmol) was dissolved
in 3 mL toluene and 2-hydroxypyridine (7 mg, 0.074 mmol)
was added. The clear, colorless solution was allowed to stir,
protected from light, for 20 h. A precipitate appeared. The
solvent was evaporated and the residue ®ltered through a
silica plug eluting with 10% MeOH in CH2Cl2. The residue
was puri®ed by HPLC (ODS, 250£10 mm, 10m, 50% H2O/
MeCN, 3 mL min21) to give 6 mg, after lyophilization, of
27 (Rtˆ9 min) as a ¯uffy colorless solid (50% yield): [a]Dˆ
29.18 (cˆ1.1, MeOH); IR (neat) 3365, 3270, 2955, 1748,
(500 MHz, CDCl3) d Unit A 7.46 (5-NH, d, 8.4), 7.25±7.34
(11/12/13-H, m), 7.22 (10/14-H, d, 6.9), 6.60 (3-H, ddd,
15.6, 7.3, 7.1), 5.54 (2-H, d, 15.6), 4.45 (8-H, d, 8.9), 3.94
(5-H, m), 3.88 (7-H, d, 8.9), 3.21 (7-OH, s), 2.52 (4-Hb, m),
2.18 (4-Ha, m), 1.32 (6-H, m), 0.95 (6-Me, d, 6.9), 0.87
(SiCMe3, s), 20.01 (SiMe, s), 20.24 (SiMe, s), Unit C
5.11 (3-NH, m), 3.37 (3-Hb, ddd, 11.9, 6.9, 5.1), 3.21
(3-Ha, m), 2.84 (2-H, m), 1.43 (NHCO2CMe3, s), 1.22
(2-Me, d, 7.1), Unit D 5.15 (2-H, bd, 8.4), 1.67 (3-H2/4-H,
bm), 0.93 (5-H3, d, 6.3), 0.92 (4-Me, d, 6.6); 13C NMR
(125 MHz, CDCl3) d Unit A 169.6 (1), 146.5 (3), 139.9
(9), 128.7 (11/12/13), 126.8 (10/14), 122.9 (2), 77.0 (8),
75.4 (7), 52.7 (5), 35.9 (4), 32.5 (6), 25.8 (SiCMe3), 18.1
(SiCMe3), 11.3 (6-Me), 24.4 (SiMe), 25.1 (SiMe), Unit C
174.4 (1), 156.0 (NHCO2CMe3), 79.6 (NHCO2CMe3), 43.4
(3), 40.2 (2), 28.4 (NHCO2CMe3), 14.4 (2-Me), Unit D
170.5 (1), 73.1 (2), 41.1 (3), 24.6 (4), 23.2 (4-Me), 21.7 (5).
1722, 1660, 1632, 1504, 1203, 1153, 1067, 1006, 699 cm21
;
Protected Seco Compound 26. To a solution of 100 mg
(0.14 mmol) of carboxylic acid 24 in 4 mL dry DMF at rt
was added FDPP (70 mg, 0.18 mmol). The mixture was
stirred for 5 min before a solution in 1 mL of DMF of
100 mg (0.25 mmol) of the hydrochloride salt of 25 and
triethylamine (45 mg, 62 mL, 0.45 mmol) was added. The
resulting mixture was stirred at rt for 5 h, diluted with
40 mL EtOAc and washed with 30 mL 0.5N HCl, 30 mL
sat. aq. NaHCO3, water and brine. The organic layer was
dried and evaporated to give a pale yellow oil. Flash
chromatography (silica, 10% EtOAc/hexane to 50%
EtOAc/hexane) produced 98 mg of fully protected seco
compound 26 as a viscous, colorless oil (69% yield):
[a]Dˆ265.68 (cˆ3.9, CHCl3); IR (neat) 3376, 2957,
2858, 1746, 1715, 1673, 1504, 1463, 1367, 1258, 1172,
1067, 837, 781, 702 cm21; FABMS (magic bullet matrix1
potassium) m/z 1078/1076/1074/1072 (M1K), 1062/1060/
1058/1056 (M1Na), 1040/1038/1036/1034 (M1H), 940/
EIMS (70 eV) m/z 671/673 (M1, ,1), 653/655 (M12H2O,
3/1), 635/637 (M122H2O, ,1), 564/566 (glycol cleavage,
1.5/0.5), 506/508 (3/1), 411/413 (4.5/1.5), 394/396 (5/2),
289/282 (19/7), 217 (74), 211/213 (53/17), 195/197 (31/
11), 184 (27), 91 (72), 77 (84), 69 (100); HREIMS m/z
671.2953 (M1, C35H46N3O8Cl D 2.0 mmu), 653.2863
(M12H2O, C35H44N3O7Cl
(M122H2O, C35H42N3O6Cl
D
D
0.4 mmu), 635.2753
0.9 mmu), 564.2493
(M12C7H7O, C28H39N3O7Cl D 21.7 mmu); 1H NMR
(500 MHz, CDCl3) d Unit A 7.27±7.37 (10/11/12/13/14-
H, m), 7.17 (5-NH, bd, 9.4), 6.63 (3-H, ddd, 15.2, 9.8,
5.4), 5.81 (2-H, d, 15.2), 4.53 (8-H, d, 8.7), 3.99 (7-H, bd,
8.7), 3.90 (5-H, m), 2.29 (4-Hb, m), 1.98 (4-Ha, m), 1.31
(6-H, m), 0.96 (6-Me, d, 6.9), Unit B 7.20 (5-H, d, 1.2), 7.07
(9-H, dd, 8.5, 1.2), 6.79 (2-NH, obs. m), 6.78 (8-H, d, 8.5),
4.77 (2-H, m), 3.81 (7-OCH3, s), 3.15 (3-Hb, dd, 14.5, 3.8),
2.89 (3-Ha, dd, 14.5, 9.2), Unit C 6.98 (3-NH, m), 3.44
(3-Hb, ddd, 13.4, 6.6, 6.5), 3.37 (3-Ha, dm, 13.4), 2.68
(2-H, m), 1.23 (2-Me, d, 7.4), Unit D 4.82 (2-H, dd, 8.9,
4.7), 1.79 (3-Hb, m), 1.72 (4-H, m), 1.52 (3-Ha, ddd, 13.0,
7.8, 4.7), 0.93 (5-H3, d, 6.5), 0.89 (4-Me, d, 6.5); 13C NMR
(125 MHz, CDCl3) d Unit A 166.2 (1), 142.3 (3), 140.3 (9),
128.8 (11/13), 128.2 (12), 127.0 (10/14), 125.0 (2), 76.0 (8),
75.0 (7), 53.6 (5), 37.3 (4), 36.6 (6), 11.4 (6-Me), Unit B
171.8* (1), 153.8 (7), 130.9 (5), 130.5 (4), 128.6 (9), 122.1
(6), 112.2 (8), 56.1 (7-OCH3), 54.2 (2), 35.3 (3), Unit C
175.7 (1), 41.1 (3), 38.9 (2), 14.3 (2-Me), Unit D 170.2p
(1), 73.0 (2), 40.6 (3), 24.5 (4), 22.8 (4-Me), 21.9 (5).
(*Assignments may be reversed.)
1
938/936/934; H NMR (500 MHz, CDCl3) d Unit A 7.40
(5-NH, bd, 7.9), 7.20±7.26 (10/11/12/13/14-H, m), 6.43
(3-H, ddd, 15.4, 7.6, 7.4), 5.40 (2-H, d, 15.4), 4.44 (8-H,
d, 8.7), 3.90 (7-H, bd, 8.7), 3.85 (5-H, m), 3.22 (7-OH, s),
2.39 (4-Hb, ddd, 14.2, 7.4, 6.8), 2.10 (4-Ha, ddd, 14.2, 7.6,
7.1), 1.36 (6-H, m), 0.94 (6-Me, d, 7.1), 0.86 (SiCMe3, s),
20.01 (SiMe, s), 20.25 (SiMe, s), Unit B 7.18 (5-H, d, 2.1),
7.05 (9-H, dd, 8.4, 2.1), 6.86 (8-H, d, 8.4), 5.95 (2-NH, bd,
7.0), 4.94 (2-H, ddd, 7.0, 6.1, 6.1), 4.76/4.70 (CH2CCl3,
AB-q, 11.8), 3.86 (7-OCH3, s), 3.15 (3-Hb, dd, 14.2, 6.1),
3.06 (3-Ha, dd, 14.2, 6.1), Unit C 5.12 (3-NH, m), 3.36
(3-Hb, m), 3.21 (3-Ha, m), 2.82 (2-H, m), 1.42
(NHCO2CMe3, s), 1.21 (2-Me, d, 7.1), Unit D 5.12 (2-H,
m), 1.59-1.71 (3-H2/4-H, bm), 0.91 (5-H3, d, 5.8), 0.90
Conversion of 27 to cryptophycin 338 (28). A sample of
10 mg of 27 was treated at rt for 2 h with 1 mL of a solution

3350
R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
3. Kobayashi, M.; Aoki, S.; Ohyabu, N.; Kurosu, M.; Wang, W.;
Kitagawa, I. Tetrahedron Lett. 1994, 35, 7969.
which was prepared from 150 mg of PPTS, and 13 mL of
trimethyl orthoformate in 41 mL of CH2Cl2. The mixture
was ®ltered through SiO2 with 80% EtOAc/hexane, and
the solvent was evaporated. The residue was evacuated for
3 h, redissolved in 0.5 mL CH2Cl2, and treated at rt with
60 mL of a 0.80 M solution of acetyl bromide in CH2Cl2.
After 6 h the reaction was quenched with 1 mL aq. NaHCO3
and partitioned between water and CH2Cl2. The organic
phase was dried (Na2SO4) and evaporated, and pumped to
dryness to provide crude formyloxy bromide. This material
was dissolved in a mixture of 300 mL DME, 200 mL EtOH
and 50 mL MeOH. To this solution was added 20 mg
KHCO3, and the heterogeneous mixture was stirred
vigorously at 408C for 15 h. The mixture was cooled to rt,
diluted with 5 mL EtOAc and ®ltered. Solvent evaporation
followed by ¯ash column chromatography on SiO2 (25%
EtOAc/CH2Cl2) provided 6 mg (62% yield) of 28 as an
amorphous solid: [a]Dˆ1208 (cˆ0.50, MeOH); IR (CCl4)
4. Barrow, R. A.; Hemscheidt, T.; Liang, J.; Paik, S.; Moore, R. E.;
Tius, M. A. J. Am. Chem. Soc. 1995, 117, 2479.
5. Salamonczyk, G. M.; Han, K.; Guo, Z.; Sih, C. J. J. Org. Chem.
1996, 61, 6893.
6. Gardinier, K. M.; Leahy, J. W. J. Org. Chem. 1997, 62, 7098.
7. Kobayashi, M.; Kurosu, M.; Wang, W.; Kitagawa, I. Chem.
Pharm. Bull. 1994, 42, 2394.
Â
8. (a) Rej, R., Nguyen, D., Go, B., Fortin, S., Lavallee, J.-F. J. Org.
Chem. 1996, 61, 6289. (b) Ali, S. M., George, G. I. Tetrahedron
Lett. 1997, 38, 1703. (c) Dhokte, U. P., Khau, V. V., Hutchison,
D. R., Martinelli, M. J. Tetrahedron Lett. 1998, 39, 8771. (d) White,
J. D., Hong, J., Robarge, L. A. Tetrahedron Lett. 1998, 39, 8779.
(e) Fray, A. H. Tetrahedron: Asymmetry 1998, 39, 2777.
(f) Norman, B. H., Hemscheidt, T., Schultz, R. M., Andis, S. L.
J. Org. Chem. 1998, 63, 5288. (g) White, J. D.; Hong, J.; Robarge,
L. A. J. Org. Chem. 1999, 64, 6206.
3416, 2956, 2875, 1655, 1449, 1314, 944, 881, 712 cm21
;
9. Golakoti, T.; Ogino, J.; Heltzel, C. E.; Le Husebo, T.; Jensen,
C. M.; Larsen, L. K.; Patterson, G. M. L.; Moore, R. E.; Mooberry,
S. L.; Corbett, T. H.; Valeriote, F. A. J. Am. Chem. Soc. 1995, 117,
12030.
EIMS (70 eV) m/z 655 (M112, 1.3), 653 (M1, 2.9), 551
(0.6), 498 (1.1), 430 (2.2), 315 (3.9), 259 (26.3), 220 (10.3),
155 (25.4), 107 (100); HREIMS m/z 653.2864 (M1,
1
10. Gage, J. R.; Evans, D. A. Org. Synth. 1989, 69, 83.
11. (a) Nahm, S., Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815. (b) Levin, J. I., Turos, E., Weinreb, S. M. Synth. Commun.
1982, 12, 989. For a review, see: Sibi, M. P. Org. Prep. Proc.
Intern. 1993, 25, 15. Initially, it had appeared to us that this
C35H44N3O7Cl D 6.0 mmu); H NMR (500 MHz, CD3OD)
d Unit A 7.45±7.35 (10/14-H, m), 7.35±7.27 (11/12/13-H,
m), 6.48 (3-H, dt, 16.0, 6.8), 5.96 (2-H, d, 16.0), 4.99 (8-H,
d, 7.0), 3.88±3.85 (5-H, m), 3.62±3.54 (4-H17-H, m), 2.45
(4-H, dd, 15.5, 6.3), 2.15±2.05 (6-H, m), 1.12 (6-Me, d, 6.3),
Unit B 7.28 (5-H, d, 1.9), 7.17 (9-H, dd, 8.5, 1.9), 6.99 (8-H,
d, 8.5), 4.36 (2-H, dd, 10.4, 4.6), 3.85 (OMe, s), 3.16 (3-Hb,
dd, 14.3, 4.6), 2.96 (3-Ha, dd, 14.3, 10.7), Unit C 3.47±3.37
(3-H, m), 2.75±2.65 (2-H, m), 1.14 (2-Me, d, 7.3), Unit D
4.76 (2-H, dd, 10.9, 2.4), 1.56 (3-Hb, ddd, 15.3, 11.1, 4.9),
1.25±1.17 (4-H, m), 0.59 (5-H3, d, 6.3), 0.50 (3-Ha, ddd,
14.1, 9.0, 2.4), 0.17 (4-Me, d, 6.5); 13C NMR (125 MHz,
CDCl3) d Unit A 169.9 (1), 140.2 (3), 132.4 (9), 130.5 (11/
13), 129.2 (12), 128.0 (2), 127.9 (10/14), 86.0 (7), 71.3 (8),
56.6 (5), 44.2 (6), 32.2 (4), 14.5 (6-Me), Unit B 174.2 (1),
155.4 (7), 144.6 (6), 131.7 (5), 129.5 (9), 123.3 (4), 113.5
(8), 65.7 (7-OMe), 57.9 (2), 35.9 (3), Unit C 176.9 (1), 41.4
(3), 39.9 (2), 14.5 (2-Me), Unit D 171.6 (1), 73.0 (2), 39.3
(3), 24.9 (4), 23.3 (4-Me), 21.3 (5).
1
reaction had failed, since the H NMR spectrum revealed only a
single resonance in the region where both OCH3 and NCH3 reso-
nances were expected. Integration showed that this single broad
peak accounted for six hydrogen atoms, however, we are aware of
no other example in which the OCH3 and NCH3 resonances of
Weinreb amides are coincident.
12. (a) Makin, S. M., Raifel'd, Y. E., Limanova, O. V.,
Shavrygina, O. A., Kosheleva, L. M. J. Org. Chem. USSR 1979,
1665. (b) Trost, B. M., Dumas, J., Villa, M. J. Am. Chem. Soc.
1992, 114, 9836.
13. (a) Masamune, S., Choy, W., Kerdesky, F. A. J., Imperiali, B.
J. Am. Chem. Soc. 1981, 103, 1566. (b) Evans, D. A., Nelson, J. V.,
Vogel, E., Taber, T. R. J. Am. Chem. Soc. 1981, 103, 3099.
14. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, S. Tetrahedron Lett. 1984, 25,
2183.
15. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
16. Papa, A. J. J. Org. Chem. 1966, 31, 1426.
Acknowledgements
17. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092.
This research was supported by Grant No. 12623 from the
National Cancer Institute, Department of Health and Human
Services and a grant from Eli Lilly & Co. We thank
Professor Thomas Hemscheidt for many helpful dis-
cussions, and Mr. Wesley Yoshida for performing the 2D
NMR experiments. M. A. T. acknowledges a Fellowship
from the Japan Society for the Promotion of Science.
18. (a) Rychnovsky, S. D., Skalitzky, D. J. Tetrahedron Lett. 1990,
31, 945. (b) Rychnovsky, S. D., Rogers, B., Yang, G. J. Org. Chem.
1993, 58, 3511.
19. Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J. Org.
Chem. 2000, 65.
20. Fieser, L. F., Fieser, M., Eds.; Wiley: New York, 1967; Vol. 1,
p 191.
21. Bonner, W. A. J. Am. Chem. Soc. 1951, 73, 3126.
22. Dibutylboron tri¯ate was obtained from Aldrich Chemical Co.
as a 1 M solution in CH2Cl2.
References
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.
23. The reaction does not proceed in scrupulously anhydrous THF.
It is necessary to add a small amount of water to the solvent in
order for the reaction to proceed.
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. This compound is not very stable, being prone to cyclise to a
THF compound with a trace of base, and is used immediately. If
the compound is to be stored, it must be kept in solution at 2108C.

R. A. Barrow et al. / Tetrahedron 56 (2000) 3339±3351
3351
25. This compound it not very stable, being prone to cyclise to a
THF compound with a trace of base, and is used immediately. If
the compound is to be stored, it should be kept in solution and kept
cold.
yield was low, which suggests that partitioning between the two
phases was incomplete. The use of crude material results in a good
overall yield of 23.
27. Air must be rigorously excluded from this reaction.
26. Although 21 could be isolated in an acid/base extraction, the