Flexible routes to the 5-hydroxy acid fragment of the cryptophycins

Article abstract of DOI:10.1002/ejoc.200210695

Two solutions to establishing the anti stereochemistry of the vicinal stereocenters in the 5-hydroxy acid subunit of cryptophycin, based on initial Evans syn aldol reactions between an N-(propionyl)oxazolidinone 4 and a C₃ aldehyde, were developed. In the first route, the secondary hydroxy group was inverted by use of Mitsunobu reaction conditions, whereas the second route features an inversion of the methyl-bearing stereocenter, achieved by reductive removal of the chiral auxiliary, elimination to afford the terminal alkene, and anti-selective hydroboration. The aryl part can be attached either by Wittig-Horner olefination or by a modified Julia coupling. Both routes provide the hydroxy acid 16 in a very efficient manner. The substrate for the hydroboration, alkene 22, could also be obtained from (S)-malic acid. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200210695

FULL PAPER
Flexible Routes to the 5-Hydroxy Acid Fragment of the Cryptophycins
Prodeep Phukan,[a] Sanjita Sasmal,[a] and Martin E. Maier*[a]
Keywords: Aldol reaction / Alkenes / Asymmetric synthesis / Hydroboration
Two solutions to establishing the anti stereochemistry of the
vicinal stereocenters in the 5-hydroxy acid subunit of crypt-
ophycin, based on initial Evans syn aldol reactions between
an N-(propionyl)oxazolidinone 4 and a C3 aldehyde, were
developed. In the first route, the secondary hydroxy group
was inverted by use of Mitsunobu reaction conditions,
whereas the second route features an inversion of the
methyl-bearing stereocenter, achieved by reductive removal
of the chiral auxiliary, elimination to afford the terminal
alkene, and anti-selective hydroboration. The aryl part can
be attached either by Wittig−Horner olefination or by a modi-
fied Julia coupling. Both routes provide the hydroxy acid 16
in a very efficient manner. The substrate for the hydrobor-
ation, alkene 22, could also be obtained from (S)-malic acid.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
Interference with microtubule assembly and disassembly
during cell division by specific small molecules has emerged
as a promising strategy in cancer therapy.[1Ϫ3] Some com-
pounds Ϫ such as taxol, the epothilones, or discodermolide
Ϫ stabilize microtubuli. On the other hand, compounds
such as vinblastine, colchicine, or podophyllotoxin shift the
microtubuli-tubulin equilibrium towards the tubulin pro-
tein. These kinds of compounds are supplemented by the
cryptophycins, which encompass a family of about 20
macrocyclic depsipeptides.[4Ϫ7] The first representative of
these depsipeptides, cryptophycin-1 (1), was isolated from
the blue-green algae Nostoc sp. ATCC 53789 in 1990.[8]
Cryptophycin-1 (1) stops the cell cycle at the G2/M-transis-
tion by inhibition of tubulin polymerization into micro-
tubules.[9] However, the binding site seems to be different
from the colchicine site. A further notable feature is that
the cryptophycins are only minimally affected by multiple
drug resistance in comparison with other antimitotic ag-
ents.
As depsipeptides, the cryptophycins are of particular
interest in the context of the synthesis of natural product-
like libraries. Thanks to their modular structures, they are
ideally suited for structural variations. We have already
demonstrated this strategy for the solid-phase assembly of
hapalosin analogues.[10] Key to the solid-phase assembly of
depsipeptides are the Fmoc protecting group for amino
groups and acid-labile or silicon-based protecting groups
for hydroxy functions. The synthesis of the more compli-
cated subunits can be performed in solution. Retrosyn-
thetically, the cryptophycins can be divided into four units.
Figure 1. Structures of representative cryptophycins
Two subunits are derived from amino acids, one from an α-
oxo acid, whereas the hydroxy acid (part A) originates from
a polyketide. A synthesis of subunit A has to address the
attachment of the aryl ring and the establishment of the anti
stereorelationship at C-5 and C-6. The epoxide in section A
may be derived either from the corresponding alkene (I) or
from a syn-diol precursor (II). Depending on this, different
strategies for dealing with the stereochemical issue have
been developed. Thus, the anti stereochemistry can be set
by epoxide opening,[11Ϫ13] by a syn aldol reaction followed
by reduction of the carboxylate to a methyl group,[14,15] by
crotylboration of an aldehyde,[16,17] by nucleophilic addition
to a 2-methyl aldehyde,[18] by Frater alkylation of a 3-
hydroxy ester,[17] or by a [2,3]-Wittig rearrangement.[19] If a
diol precursor such as II is targeted, aldol strategies[20] or
nucleophilic additions to the aldehyde derived from man-
[a]
Institut für Organische Chemie, Universität Tübingen,
Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax: (internat.) ϩ 49-7071/295137
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DOI: 10.1002/ejoc.200200695
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P. Phukan, S. Sasmal, M. E. Maier
FULL PAPER
delate are possible.[21Ϫ23] In these cases the stereochemistry
of one secondary alcohol is set by a directed reduction.
We sought to develop a route that is simple to perform
and that allows for flexible introduction of an aryl or heta-
ryl group by cross-coupling and Julia or Wittig olefination.
In this paper we illustrate two aldol approaches that invert
either one of the stereocenters. Route 1 utilizes a Mitsunobu
reaction, whereas route 2 is based on an anti-selective
hydroboration of an alkyl 2-methylprop-2-enyl ether. In a
utilization of Evans’ aldol methodology,[24Ϫ26] the N-propi-
onyloxazolidinone 4 was treated with the aldehyde 5 under
standard conditions to give the syn aldol product 6. After
reductive removal of the chiral auxiliary with sodium
borohydride,[27] the diol 7 was obtained, and its primary
hydroxy group was temporarily protected by silylation with
tert-butyldimethylsilyl chloride to allow the inversion of the
secondary hydroxy group by treatment with p-nitrobenzoic
acid in the presence of diisopropyl azodicarboxylate
(DIAD) and triphenylphosphane.[28] Basic ester hydrolysis
delivered the alcohol 10. Extension of the carbon chain on
the other terminus necessitated protection of the secondary
alcohol as its tert-butyldimethyl silyl ether, giving com-
pound 11, subsequent oxidative removal of the p-meth-
oxybenzyl group furnishing alcohol 12.[29,30] Two straight-
Scheme 1. Synthesis of the key building block 12 by Evans aldol
reaction and inversion of the secondary alcohol by Mitsunobu re-
action: a) nBu2BOTf, iPr2NEt, CH2Cl2, Ϫ78 to 23 °C, 2.5 h, 82%;
b) NaBH4, THF/H2O (5:1), 0 to 25 °C, 2 h, 76%; c) TBDMSCl,
NEt3, DMAP (cat.), CH2Cl2, 0 to 23 °C, 12 h, 95%; d) PPh3,
forward steps, first
a Swern oxidation and then a
HornerϪWadsworthϪEmmons reaction between the re-
sulting aldehyde and ethyl diethylphosphonoacetate, pro-
vided enoate 13 in good overall yield. Construction of the iPrO2CNϭNCO2iPr, 4-O2NC6H4CO2H, THF, 0 to 23 °C, 12 h,
70%; e) NaOH, MeOH, 23 °C, 2 h, 94%; f) TBDMSCl, imidazole,
styrene part began with the selective cleavage of the primary
DMF, 23 °C, 12 h, 87%; g) DDQ, CH2Cl2/H2O (20:1), 0 to 23 °C,
silyl ether to afford alcohol 14. Swern oxidation[31] and a
2.5 h, 85%; h) (COCl)2, DMSO, CH2Cl2, Ϫ78 °C, 1 h, NEt3, Ϫ78
to 0 °C, 2 h; i) (EtO)2P(O)CH2CO2Et, NaH, THF, 0 to 23 °C, add
aldehyde, 0 °C, 1 h, 95% (2 steps); j) AcOH/H2O/THF (1:1:2),
23 °C, 50 h, 75%; k) (COCl)2, DMSO, CH2Cl2, Ϫ78 °C, 1 h, NEt3,
Ϫ78 to 0 °C, 3 h; l) (EtO)2P(O)CH2Ph (15), nBuLi, THF, Ϫ78 °C,
1 h, add aldehyde, Ϫ78 to 23 °C, 7 h; 56% (2 steps)
Wittig reaction between the obtained aldehyde and the
phosphonate 15 gave the target compound 16. As can be
judged from the 1H and 13C NMR spectra, the dia-
stereomeric purity of this compound was very high.
The second route started from the aldehyde 17[32] and is
also based on an Evans aldol reaction. In this case, how- subjected to a Swern oxidation, and the aldehyde was ex-
ever, the enantiomeric oxazolidinone (ent-4) derived from tended by Wittig olefination,[38] also to give the enoate 16.
-phenylalanine was used (Scheme 2). Protection of the
In the course of this work an alternative synthesis of al-
hydroxy group in 18 with tert-butyldimethylsilyl triflate/luti- kene 22 was developed. This route started with (S)-malic
dine was followed by reductive removal[27] of the auxiliary, acid (29), a compound featuring a secondary hydroxy group
affording 20. Next, a terminal double bond had to be intro- (Scheme 3). As has been described by Schinzer’s group,[39]
duced. This was accomplished in high yield by the method protection of 29 with cyclohexanone, selective reduction of
we had previously described.[33] Thus, tosylation of the al- the acid group of the lactone 30 with boraneϪdimethyl sulf-
cohol 20 and subsequent heating of the tosylate 21 at reflux ide, and lactonization gave rise to the 2-hydroxy lactone
in glyme (1,2-dimethoxyethane) in the presence of NaI (2.5 31.[40] In this sequence it is very important to perform the
equiv.) and DBU (5.0 equiv.) effected clean elimination to reduction very slowly in order to assure a good chemical
provide the disubstituted allyl ether 22. The stereocenter de- yield of compound 31. After protection of the hydroxy
stroyed in this process was reintroduced by diastereoselec- group as its silyl ether, treatment of the lactone 32 with
tive hydroboration,[34,35] which gave the anti product 23 methyllithium yielded the known methyl ketone 33. Finally,
with high diastereoselectivity (9:1). In this case, the intro- an olefination reaction gave the known alkene 22.[41]
duction of the styrene component was performed by means
In summary, we have developed two syntheses of 16, a
of a Julia olefination.[36,37] Accordingly, the primary alcohol protected building block for the 5-hydroxy acid fragment
was converted into the sulfide 24 under Mitsunobu con- of the cryptophycins. Both routes feature an inversion of a
ditions, oxidation of 24 furnished the sulfone 25, and depro- stereocenter. The facile conversion of syn aldol products
tonation of the sulfone [KN(SiMe3)2, THF, Ϫ78 °C] and such as 6 or 18 into derivatives featuring an anti stereorel-
subsequent addition of benzaldehyde directly gave the (E)- ationship at the two stereocenters provides an easy route to
alkene 26. To conclude the synthesis, the primary trialkylsi- this chiral moiety. In one approach the secondary hydroxy
lyl ether was cleaved, the resulting primary alcohol 27 was group was inverted by use of a Mitsunobu reaction, whereas
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Eur. J. Org. Chem. 2003, 1733Ϫ1740

Flexible Routes to the 5-Hydroxy Acid Fragment of the Cryptophycins
FULL PAPER
the second route features an inversion of the methyl-bearing
stereocenter by hydroboration of a terminal 2,2-disubsti-
tuted double bond. Both routes are flexible enough to allow
for variations in the aryl part. Studies to further elaborate
building block 16 into cryptophycin analogues are un-
derway in our laboratory.
Experimental Section
General: 1H and 13C NMR: Bruker Avance 400, spectra were re-
corded in CDCl3; chemical shifts are calibrated to the residual pro-
ton and carbon resonance of the solvent: CDCl3 (δH ϭ 7.25 ppm,
δC ϭ 77.00 ppm). Melting points: Büchi Melting Point B-540, un-
corrected values. Polarimeter: JASCO Polarimeter P-1020. IR:
Jasco FT/IR-430. EI-MS: Finnigan Triple-Stage-Quadrupole
(TSQ-70). HR-MS (EI): Modified AMD Intectra MAT 711 A.
HPLC-MS (API-ES): Agilent 1100 Series LC/MSD. HR-MS (FT-
ICR): Bruker Daltonic APEX 2 with electrospray ionization (ESI).
Flash chromatography: J. T. Baker silica gel 43Ϫ60 µm. Thin-layer
chromatography Macherey-Nagel Polygram Sil G/UV254. Solvents
were distilled prior to use; petroleum ether with a boiling range of
40Ϫ60 °C was used.
(4S)-4-Benzyl-3-{(2S,3R)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2-
methylpentanoyl}-1,3-oxazolidin-2-one (6):[42,43] Di-n-butylboron
triflate (1  in CH2Cl2, 29.5 mL, 29.5 mmol) was added at 0 °C to
a solution of imide 4[24] (6.3 g, 27 mmol) in CH2Cl2 (60 mL), fol-
lowed by the dropwise addition of Hünig’s base (5.5 mL,
31.9 mmol). After stirring at 0 °C for 1 h, the reaction mixture was
cooled to Ϫ78 °C and a solution of 3-(p-methoxybenzyloxy)pro-
panal[17,44,45] (5, 4.8 g, 24.6 mmol) in CH2Cl2 (10 mL) was added
dropwise. The resulting pale yellow solution was stirred at Ϫ78 °C
for 1.5 h, then allowed to warm to 0 °C over 30 min, and stirred at
0 °C for 30 min. The reaction was quenched by the addition of
phosphate buffer (pH ϭ 7, 33 mL) followed by methanol (120 mL),
resulting in a homogeneous solution. After 5 min, 33 mL of 30%
aqueous hydrogen peroxide in methanol (50 mL) was added drop-
wise over 30 min. After having been stirred at 0 °C for 1 h, the
reaction mixture was concentrated by rotary evaporation. The re-
sulting mixture was extracted with EtOAc (3 ϫ 100 mL). The or-
ganic extracts were washed with HCl (1 , 100 mL), aqueous
NaHCO3 (5%, 100 mL), and brine (100 mL), dried (Na2SO4), fil-
tered, and concentrated. The crude product was purified by flash
chromatography (40% EtOAc in petroleum ether) to provide the
aldol product 6 (9.5 g, 82% yield) as a colorless, viscous liquid.
[α]2D3 ϭ ϩ42.4 (c ϭ 1.81, CH2Cl2). IR (neat): ν˜ ϭ 3515 (br.), 2936,
Scheme 2. Synthesis of the enoate 16 by Evans aldol reaction and
inversion of the methyl bearing stereocenter by elimination and
hydroboration: a) TiCl4, sparteine, CH2Cl2, 0 °C, 25 min, add alde-
hyde, 0 °C, 1 h, 87%; b) TBDMSOTf, 2,6-lutidine, CH2Cl2, 23 °C,
12 h, 93%; c) NaBH4, THF/H2O (5:1), 0 to 25 °C, 2 h, 75%; d)
pTsCl, pyridine, 0 °C, 95%; e) NaI, DBU, glyme, reflux, 3 h, 95%;
f) 9-BBN, THF, 0 to 23 °C, 3 h, then H2O2, NaOH, 83%; g) 1-
phenyl-1H-tetrazole-5-thiol, PPh3, iPrO2CNϭNCO2iPr, DMF, 0 to
23 °C, 30 min, 84%; h) mCPBA, CH2Cl2, 0 to 23 °C, 3 h, 76%; i)
KN(SiMe3)2, glyme, Ϫ55 °C, 40 min, add aldehyde, Ϫ55 to 23 °C,
4 h, 70%; j) PPTS, MeOH, 50 °C, 4 h, 86%; k) (COCl)2, DMSO,
CH2Cl2, Ϫ60 °C, 40 min, NEt3, Ϫ60 to 0 °C, 2 h, add Ph3Pϭ
CHCO2Et, 23 °C, 12 h, 78%
1781, 1695, 1514, 1247 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ
.
7.36Ϫ7.20 (m, 7 H), 6.88 (d, J ϭ 8.7 Hz, 2 H), 4.69 (ddd, J ϭ 3.3,
6.8, 9.8 Hz, 1 H), 4.45 (s, 2 H), 4.22Ϫ4.16 (m, 3 H), 3.85Ϫ3.78 (m,
1 H), 3.80 (s, 3 H), 3.72Ϫ3.61 (m, 2 H), 3.26 (dd, J ϭ 3.2, 13.6 Hz,
1 H), 2.89 (dd, J ϭ 9.5, 13.4 Hz, 1 H), 1.90Ϫ1.83 (m, 1 H),
1.78Ϫ1.72 (m, 1 H), 1.29 (d, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 176.5, 159.1, 153.0, 135.1, 130.0, 129.4,
129.3, 128.9, 127.3, 113.7, 72.8, 70.4, 68.0, 66.1, 55.18, 55.15, 42.5,
37.7, 33.6, 11.4 ppm. MS (EI): m/z (%) ϭ 426 (2), 306 (4), 290 (15)
176 (30), 137 (80), 121 (100). HRMS (FT-ICR): calcd. for
C24H29NO6Na 450.1887, found 450.1883.
Scheme 3. Synthesis of the alkene 22 from (S)-malic acid (29): a)
cyclohexanone (1 equiv.), BF3·OEt2 (1.5 equiv.), Et2O, 0.35 , 0
°C, 1 h, 23 °C, 10 h, 98%; b) BH3·SMe2 (2.9 equiv.), (MeO)3B (2.9
equiv.), THF, 0.2 , 0 to 23 °C, 24 h, coevaporation with MeOH;
c) CH2Cl2, 0.3 , pTsOH H2O (0.1 equiv.), 23 °C, 24 h (68%); d)
TBDMSCl (1.1 equiv.), imidazole (2.0 equiv.), DMF, 1.4 , 23 °C,
24 h, 92%; e) MeLi (1.1 equiv.), THF, Ϫ78 °C, 3 h; f) TBDMSCl
(1.1 equiv.), imidazole (2.0 equiv.), DMF, 0.8 , 23 °C, 24 h, 65%
(2 steps); g) Ph3PCH3ϩBrϪ, nBuLi, THF, 0 °C, add 33, 0 to 23 °C,
48 h, 48%
(2R,3R)-5-[(4-Methoxybenzyl)oxy]-2-methylpentane-1,3-diol
(7):
NaBH4 (5.4 g, 140 mmol) was added portionwise at 0 °C to a
stirred solution of the aldol adduct 6 (12.0 g, 28.1 mmol) in THF
and water (180 mL, 5:1). The reaction mixture was stirred at 0 °C
for 5 min and was then allowed to warm to 25 °C. After having
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P. Phukan, S. Sasmal, M. E. Maier
FULL PAPER
been stirred at room temperature for 2 h, the reaction mixture was 72.7, 66.6, 64.5, 55.1, 39.3, 31.0, 25.8, 18.2, 12.8, Ϫ5.55, Ϫ5.59
quenched with HCl solution (2 , 70 mL) and extracted with
EtOAc (3 ϫ 200 mL). The combined organic layers were washed
ppm. MS (API-ES, 90 V): m/z (%) ϭ 540 (100) [M ϩ Na]ϩ, 391
(20), 121 (60). HRMS (FT-ICR): calcd. for C27H39NO7SiNa
with saturated NaHCO3 solution (100 mL), water (100 mL), and 540.2388, found 540.2385.
brine (100 mL), dried (Na2SO4), filtered, and concentrated to give
(2R,3S)-1-{[(tert-Butyl)dimethylsilyl]oxy}-5-[(4-methoxybenzyl)-
the crude product, which was purified by flash chromatography
(60% EtOAc in petroleum ether) to give the diol 7 (5.41 g, 76%
yield) as a colorless, viscous liquid. [α]2D4 ϭ Ϫ10.4 (c ϭ 0.80,
oxy]-2-methylpentan-3-ol (10): A solution of the ester 9 (2.34 g,
4.52 mmol) in MeOH (15 mL) was treated with NaOH (0.9 g,
22.58 mmol) and the reaction mixture was stirred at room tempera-
ture for 2 h. After completion of the reaction (monitored by TLC),
the reaction mixture was treated with water (50 mL) and extracted
with EtOAc (3 ϫ 75 mL). The combined organic layers were
washed with water (2 ϫ 50 mL) and brine (50 mL), dried (Na2SO4),
filtered, and concentrated. The residue was purified by flash chro-
matography (20% EtOAc in petroleum ether) to give the pure anti
isomer 10 (1.57 g, 94% yield) as a colorless liquid. [α]2D5 ϭ Ϫ9.7
(c ϭ 0.78, CH2Cl2). IR (neat): ν˜ ϭ 3498 (br.), 2955, 2857, 1513,
1249 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 7.27 (d, J ϭ 8.6 Hz,
2 H), 6.88 (d, J ϭ 8.6 Hz, 2 H), 4.46 (s, 2 H), 3.80 (s, 3 H),
3.76Ϫ3.60 (m, 5 H), 1.87Ϫ1.80 (m, 1 H), 1.78Ϫ1.68 (m, 2 H), 0.90
(s, 9 H), 0.88 (d, J ϭ 7.1 Hz, 3 H), 0.80 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 159.1, 130.4, 129.3, 113.7, 74.2, 72.8, 68.1,
67.5, 55.2, 40.2, 34.6, 25.8, 18.1, 13.4, Ϫ5.58, Ϫ5.64 ppm. MS (EI):
m/z (%) ϭ 369 (5) [M]ϩ, 261 (15), 137(20), 121 (100). HRMS (EI):
calcd. for C20H36O4Si 368.2392, found 368.2383.
CH2Cl2). IR (neat): ν˜ ϭ 3407 (br.), 2876, 1613, 1515, 1249 cmϪ1
.
1H NMR (400 MHz, CDCl3): δ ϭ 7.26 (d, J ϭ 8.4 Hz, 2 H), 6.89
(d, J ϭ 8.4 Hz, 2 H), 4.46 (s, 2 H), 4.02 (dt, J ϭ 2.7, 10.1 Hz, 1
H), 3.81 (s, 3 H), 3.73 (ddd, J ϭ 4.8, 4.8, 9.3 Hz, 1 H), 3.68Ϫ3.62
(m, 3 H), 3.22 (s, 2 H), 1.92Ϫ1.81 (m, 2 H), 1.62 (dddd, J ϭ 2.4,
4.8, 4.8, 14.4 Hz, 1 H), 0.9 (d, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 159.2, 129.8, 129.3, 113.8, 74.7, 73.0, 69.5,
66.6, 55.2, 39.4, 32.7, 10.9 ppm. MS (EI): m/z (%) ϭ 254 (4) [M]ϩ,
235 (8), 177 (15), 137 (92), 121 (100). HRMS (EI): calcd. for
C14H22O4 254.1518, found 254.1509.
(2R,3R)-1-{[(tert-Butyl)dimethylsilyl]oxy}-5-[(4-methoxybenzyl)-
oxy]-2-methylpentan-3-ol (8): Et3N (3.3 mL, 25.2 mmol), TBSCl
(2.3 g, 15.1 mmol), and 4-(dimethylamino)pyridine (DMAP, 77 mg,
0.63 mmol) were added to a cooled (0 °C) solution of the diol 7
(3.2 g, 12.6 mmol) in CH2Cl2 (60 mL). The mixture was stirred at
room temperature overnight and was then quenched with water.
The organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2 (2 ϫ 50 mL). The combined organic layers
were washed with water (50 mL) and brine (50 mL), dried
(Na2SO4), filtered, and concentrated to give the crude product,
which was purified by flash chromatography (20% EtOAc in petro-
leum ether) to provide the silyl ether 8 (4.4 g, 95% yield) as a color-
less oil. [α]2D6 ϭ Ϫ0.82 (c ϭ 1.84, CH2Cl2). IR (neat): ν˜ ϭ 3504,
(2R,3S)-1,3-Bis{[(tert-butyl)dimethylsilyl]oxy}-5-[(4-methoxy-
benzyl)oxy]-2-methylpentane (11): TBSCl (0.82 g, 5.4 mmol) and
imidazole (0.55 g, 8.1 mmol) were added to a solution of alcohol
10 (1.0 g, 2.7 mmol) in DMF (5 mL) and the reaction mixture was
stirred at room temperature overnight. It was then treated with
saturated aqueous NH4Cl solution (10 mL) and partitioned be-
tween Et2O (50 mL) and water (50 mL). The diethyl ether layer was
washed with water (20 mL) and brine (20 mL), dried (Na2SO4),
filtered, and concentrated. The residue was purified by flash chro-
matography (10% EtOAc in petroleum) to give the pure product 11
(1.14 g, 87% yield) as a colorless liquid. [α]2D5 ϭ Ϫ8.6 (c ϭ 1.16,
2954, 2857, 1513, 1250 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ
.
7.28 (d, J ϭ 8.7 Hz, 2 H), 6.89 (d, J ϭ 8.7 Hz, 2 H), 4.47 (s, 2 H),
3.98Ϫ3.94 (dt, J ϭ 2.9, 9.8 Hz, 1 H), 3.81 (s, 3 H), 3.73Ϫ3.62 (m,
4 H), 1.83Ϫ1.79 (m, 1 H), 1.74Ϫ1.66 (m, 2 H), 0.93 (d, J ϭ 7.2 Hz,
3 H), 0.91 (s, 9 H), 0.08 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 159.1, 130.3, 129.2, 113.7, 72.7, 72.3, 68.3, 67.5, 55.2,
39.6, 34.0, 25.8, 18.1, 10.6, Ϫ5.63, Ϫ5.67 ppm. MS (API-ES, 90
V): m/z (%) ϭ 391 (95) [M ϩ Na]ϩ, 277 (12), 121 (100). HRMS
(FT-ICR): calcd. for C20H36O4SiNa 391.2275, found 391.2273.
CH2Cl2). IR (neat): ν˜ ϭ 2955, 2857, 1514, 1249 cmϪ1 1H NMR
.
(400 MHz, CDCl3): δ ϭ 7.23 (d, J ϭ 8.8 Hz, 2 H), 6.85 (d, J ϭ
8.8 Hz, 2 H), 4.40 (ABq, J ϭ 11.6, 2 H), 3.87 (ddd, J ϭ 4.3, 4.3,
7.5 Hz, 1 H), 3.78 (s, 3 H), 3.55Ϫ3.45 (m, 3 H), 3.38 (dd, J ϭ 6.3,
10.1 Hz, 1 H), 1.81 (dddd, J ϭ 6.8, 6.8, 11.6, 13.6 Hz, 1 H),
1.74Ϫ1.61 (m, 2 H), 0.86Ϫ0.85 (2 s, 18 H), 0.82 (d, J ϭ 6.8 Hz, 3
H), 0.02Ϫ0.00 (4 s, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
159.0, 130.7, 129.2, 113.7, 72.5, 70.1, 67.2, 65.1, 55.2, 41.5, 32.3,
25.90, 25.87, 18.2, 18.1, 11.7, Ϫ4.5, Ϫ4.7, Ϫ5.4, Ϫ5.5 ppm. MS
(EI): m/z (%) ϭ 337 (4), 281 (6), 221 (10), 147 (100), 121 (90).
HRMS (FT-ICR): calcd. for C26H50O4Si2Na 505.3140, found
505.3143.
(1S,2R)-3-{[(tert-Butyl)dimethylsilyl]oxy}-1-{2-[(4-methoxybenzyl)-
oxy]ethyl}-2-methylpropyl 4-Nitrobenzoate (9): Triphenylphosphane
(6.6 g, 25 mmol), diisopropyl azodicarboxylate (4.95 mL,
25 mmol), and then p-nitrobenzoic acid (4.18 g, 25 mmol) were ad-
ded with stirring to a cooled (0 °C) solution of compound 8 (4.6 g,
12.5 mmol) in THF (50 mL). The reaction mixture was then stirred
at room temperature overnight, diluted with diethyl ether (100 mL),
and quenched with saturated NaHCO3 (100 mL). The organic layer
was separated, and the aqueous layer was extracted with Et2O (2
(3S,4R)-3,5-Bis{[(tert-butyl)dimethylsilyl]oxy}-4-methylpentan-1-ol
(12): DDQ (0.730 g, 3.2 mmol) was added at 0 °C to a stirred solu-
ϫ 50 mL). The combined organic layers were washed with water tion of diethyl ether 11 (1.4 g, 2.9 mmol) in a mixture of CH2Cl2
(50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concen- and water (21 mL, 20:1). After the mixture had been stirred for
trated. The residue was purified by flash chromatography (10%
EtOAc in petroleum ether) to provide the benzoate 9 (4.53 g, 70%
yield) as a light yellow liquid. [α]2D6 ϭ Ϫ14.5 (c ϭ 1.58, CH2Cl2).
30 min at 0 °C, the cooling bath was removed and the mixture was
stirred for an additional 2 h. It was then diluted with CH2Cl2
(20 mL), and the layers were separated. The organic layer was
IR (neat): ν˜ ϭ 2955, 2857, 1724, 1528, 1276 cmϪ1 1H NMR washed with saturated NaHCO3 solution (2 ϫ 10 mL), dried
.
(400 MHz, CDCl3): δ ϭ 8.21 (d, J ϭ 9.1 Hz, 2 H), 8.11 (d, J ϭ (Na2SO4), filtered, and concentrated. The residue was purified by
9.1 Hz, 2 H), 7.15 (d, J ϭ 8.6 Hz, 2 H), 6.74 (d, J ϭ 8.6 Hz, 2 H),
5.39 (ddd, J ϭ 3.8, 5.9, 9.0 Hz, 1 H), 4.33 (s, 2 H), 3.73 (s, 3 H),
flash chromatography (15% EtOAc in petroleum ether) to give the
alcohol 12 (0.895 g, 85% yield) as a colorless, viscous liquid. [α]D25
ϭ
3.61 (dd, J ϭ 5.7, 10.1 Hz, 1 H), 3.59Ϫ3.49 (m, 3 H), 2.09 (m, 1 Ϫ7.6 (c ϭ 0.59, CH2Cl2). IR (neat): ν˜ ϭ 3267 (br.), 2885, 1462,
1
H), 2.04Ϫ1.98 (m, 2 H), 0.98 (d, J ϭ 7.1 Hz, 3 H), 0.87 (s, 9 H),
0.00 and Ϫ0.01 (2 s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 6.6 Hz, 1 H), 3.79Ϫ3.70 (m, 2 H), 3.47 (dABq, 3J ϭ 7.1, JAB
164.1, 159.0, 150.3, 136.0, 130.5, 130.1, 129.3, 123.3, 113.5, 75.0, 10.1 Hz, 2 H), 2.27 (s, 1 H), 1.97Ϫ1.87 (m, 1 H), 1.73Ϫ1.63 (m, 2
1051 cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 3.97 (dd, J ϭ 5.1,
ϭ
1736
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1733Ϫ1740

Flexible Routes to the 5-Hydroxy Acid Fragment of the Cryptophycins
FULL PAPER
H), 0.88 and 0.87 (2 s, 18 H), 0.83 (d, J ϭ 6.8 Hz, 3 H), 0.08Ϫ0.02 5.6, JAB ϭ 11.1 Hz, 1 H), 2.52Ϫ2.39 (m, 2 H), 2.12 (br. s, 1 H),
(4 s, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 72.4, 65.1, 1.78Ϫ1.69 (m, 1 H), 1.27 (t, J ϭ 7.3 Hz, 3 H), 0.97 (d, J ϭ 3 H),
60.7, 40.9, 33.7, 25.88, 25.84, 18.2, 18.0, 11.6, Ϫ4.54, Ϫ4.59, Ϫ5.41,
Ϫ5.53 ppm. MS (EI): m/z (%) ϭ 189 (45), 173 (85), 131 (45), 73 CDCl3): δ ϭ 166.2, 144.9, 123.8, 75.5, 65.1, 60.3, 38.9, 37.8, 25.8,
0.89 (s, 9 H), 0.08 and 0.07 (2 s, 6 H) ppm. 13C NMR (100 MHz,
(100). HRMS (EI): calcd. for C18H41O2Si2 345.2668, found
345.2645.
17.9, 14.23, 14.18, Ϫ4.4, Ϫ4.8 ppm. MS (API-ES, 70 V): m/z (%) ϭ
339 (45) [M ϩ Na]ϩ, 317 (95) [M]ϩ, 185 (100), 139 (70). HRMS
(FT-ICR): calcd. for C16H32O4SiNa 339.1962, found 339.1962.
Ethyl (2E,5S,6R)-5,7-Bis{[(tert-butyl)dimethylsilyl]oxy}-6-methyl-
hept-2-enoate (13)
Ethyl (2E,5S,6R,7E)-5-{[(tert-Butyl)dimethylsilyl]oxy}-6-methyl-8-
phenylocta-2,7-dienoate (16)
Step 1: (3S,4R)-3,5-Bis{[(tert-butyl)dimethylsilyl]oxy}-4-methyl-
pentanal: DMSO (0.308 mL, 4.36 mmol), dissolved in CH2Cl2 (a) From Alcohol 14. Step 1: Ethyl (2E,5S,6S)-5-{[(tert-
(1 mL), was added at Ϫ78 °C to a stirred solution of oxalyl chloride
(0.204 mL, 2.37 mmol) in CH2Cl2 (5 mL). After 5 min, alcohol 12
Butyl)dimethylsilyl]oxy}-6-methyl-7-oxohept-2-enoate:
sulfoxide (0.05 mL, 0.7 mmol), dissolved in CH2Cl2 (1 mL), was
Dimethyl
(0.715 g, 1.98 mmol) in CH2Cl2 (3 mL) was added, and the reaction added at Ϫ78 °C to a solution of oxalyl chloride (0.033 mL,
mixture was stirred at Ϫ78 °C for 1 h. Et3N (1 mL, 9.99 mmol) was
then added dropwise, and the reaction mixture was allowed to
come to 0 °C over 2 h. Water (5 mL) was then added and the layers
0.38 mmol) in CH2Cl2 (2 mL). After 5 min, alcohol 14 (0.1 g,
0.32 mmol) in CH2Cl2 (2 mL) was added to the reaction mixture
and stirring was continued at Ϫ78 °C for 1 h. Et3N (0.207 mL,
were separated. The organic layer was washed with brine (5 mL), 1.6 mmol) was then added dropwise, and the mixture was allowed
dried (Na2SO4), filtered, and concentrated to give the crude alde-
hyde, which was used for the next reaction without any further
purification.
to come to room temperature over 3 h and then treated with water
(3 mL), and the layers were separated. The aqueous layer was ex-
tracted with CH2Cl2 (2 ϫ 10 mL). The combined organic layers
were washed with brine (10 mL), dried (Na2SO4), filtered, and con-
centrated to give the crude aldehyde, which was used for the next
step without any further purification.
Step 2: Ethyl (2E,5S,6R)-5,7-Bis{[(tert-butyl)dimethylsilyl]oxy}-6-
methylhept-2-enoate: The phosphonate (EtO)2P(O)CH2CO2Et
(1.81 mL, 10.5 mmol) was added dropwise at 0 °C to a slurry of
NaH (0.21 g, 8.75 mmol) in THF (10 mL). After 30 min at 0 °C, Step 2: Ethyl (2E,5S,6R,7E)-5-{[(tert-Butyl)dimethylsilyl]oxy}-6-
the mixture was stirred at room temperature for an additional methyl-8-phenylocta-2,7-dienoate (16): nBuLi (2.5  in hexane,
30 min and recooled to 0 °C, after which the aldehyde (from the 0.168 mL, 0.42 mmol) was added at Ϫ78 °C to a solution of diethyl
previous reaction), dissolved in THF (3 mL), was added. The reac-
tion mixture was stirred at 0 °C for 1 h, and was then quenched
with a saturated aqueous solution of NH4Cl (5 mL), diluted with
water (15 mL), and extracted with Et2O (2 ϫ 30 mL). The com-
bined organic layers were washed with brine (10 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified by
flash chromatography (10% EtOAc in petroleum ether) to provide
benzylphosphonate[18] (0.133 mL, 0.64 mmol) in THF (3 mL). Stir-
ring was continued at Ϫ78 °C for 1 h, after which a solution of the
aldehyde (from the previous reaction), dissolved in THF (2 mL),
was added. After having been stirred at Ϫ78 °C for 1 h, the mixture
was allowed to warm gradually to room temperature over 6 h.
Aqueous NH4Cl solution (5 mL) was then added, and the mixture
was extracted with Et2O (2 ϫ 10 mL). The combined organic layers
were washed with water (5 mL) and brine (5 mL), dried (Na2SO4),
the enoate 13 (0.806 g, 95% yield) as a colorless liquid. [α]D26
ϭ
Ϫ2.95 (c ϭ 0.65, CH2Cl2). IR (neat): ν˜ ϭ 2928, 2857, 1725, 1472, filtered, and concentrated. The residue was purified by flash chro-
1257 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 7.03Ϫ6.95 (m, 1 H),
matography (20% EtOAc in petroleum ether) to provide the pure
5.82 (dt, J ϭ 1.3, 15.4 Hz, 1 H), 4.17 (q, J ϭ 7.1 Hz, 2 H), 3.83 dienoate 16 (0.068 g, 56% yield) as a colorless, viscous liquid.
(ddd, J ϭ 4.8, 4.8, 6.6 Hz, 1 H), 3.50 (dABq, 3J ϭ 6.8, JAB [α]D26 ϭ ϩ58.5 (c ϭ 0.63, CH2Cl2). IR (neat): ν˜ ϭ 2927, 2856, 1723,
10.1 Hz, 2 H), 2.38Ϫ2.25 (m, 2 H), 1.81 (ddd, J ϭ 6.8, 12.9,
1655, 1462, 1259 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ
ϭ
.
19.2 Hz, 1 H), 1.27 (t, J ϭ 7.1 Hz, 3 H), 0.88 and 0.87 (2 s, 18 H), 7.37Ϫ7.19 (m, 5 H), 6.96 (ddd, J ϭ 7.6, 7.6, 15.4 Hz, 1 H), 6.38
0.83 (d, J ϭ 6.8 Hz, 3 H), 0.02 (br. s, 12 H) ppm. 13C NMR (d, J ϭ 16.2 Hz, 1 H), 6.17 (dd, J ϭ 8.1, 15.9 Hz, 1 H), 5.83 (dt,
(100 MHz, CDCl3): δ ϭ 166.4, 146.8, 123.1, 72.2, 64.9, 60.1, 41.2,
36.0, 25.9, 25.8, 18.2, 18.1, 14.3, 12.0, Ϫ4.5, Ϫ4.7, Ϫ5.4, Ϫ5.5 ppm.
J ϭ 1.3, 15.9 Hz, 1 H), 4.19 (q, J ϭ 7.3 Hz, 2 H), 3.76 (ddd, J ϭ
4.0, 6.3, 6.3 Hz, 1 H), 2.48Ϫ2.44 (m, 1 H), 2.38Ϫ2.34 (m, 2 H),
MS (API-ES, 70 V): m/z (%) ϭ 453 (10) [M ϩ Na]ϩ, 431 (100) [M 1.28 (t, J ϭ 7.3 Hz, 3 H), 1.11 (d, J ϭ 7.1 Hz, 3 H), 0.91 (s, 9 H),
ϩ 1]ϩ, 299 (40), 167 (35). HRMS: calcd. for C22H46O4Si2Na
453.2827, found 453.2830.
0.07 and 0.06 (2 s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
166.4, 146.1, 137.6, 131.9, 130.4, 128.5, 127.0, 126.0, 123.3, 75.0,
60.1, 42.8, 37.5, 25.8, 18.1, 16.2, 14.2, Ϫ4.4, Ϫ4.5 ppm. MS (API-
ES, 90 V): m/z (%) ϭ 411 (75) [M ϩ Na]ϩ, 389 (10) [M]ϩ, 257 (50),
183 (100). HRMS (FT-ICR): calcd. for C23H36O3SiNa 411.2326,
found 411.2324.
Ethyl
(2E,5S,6R)-5-{[(tert-Butyl)dimethylsilyl]oxy}-7-hydroxy-6-
solution of enoate 13 (0.806 g,
methylhept-2-enoate (14):
A
1.87 mmol) in AcOH and aqueous THF (AcOH/H2O/THF 1:1:2,
16 mL) was stirred at room temperature for 50 h. The reaction mix-
ture was neutralized to pH ϭ 7 with saturated aqueous NaHCO3
solution and extracted with EtOAc (2 ϫ 20 mL). The combined
organic layers were washed with water (10 mL), dried (Na2SO4),
filtered, and concentrated. The crude product was purified by flash
chromatography (20% EtOAc in petroleum ether) to provide the
(b) From Alcohol 27: Dimethyl sulfoxide (0.033 mL, 0.47 mmol)
was added dropwise at Ϫ60 °C to a stirred solution of oxalyl chlo-
ride (0.022 mL, 0.234 mmol) in CH2Cl2 (2 mL). After 10 min, a
solution of alcohol 27 (60 mg, 0.187 mmol) in CH2Cl2 (1 mL) was
added to the reaction mixture. After 30 min, the reaction mixture
was treated with triethylamine (0.13 mL, 0.936 mmol) and allowed
to warm to 0 °C. At this point ethyl (triphenylphosphoranylidene)-
alcohol 14 (0.445 g, 75% yield) as a colorless, viscous liquid. [α]D26
ϩ15.1 (c ϭ 0.32, CH2Cl2). IR (neat): ν˜ ϭ 3469 (br.), 2929, 2857,
1722, 1471, 1257 cmϪ1
(ddd, J ϭ 7.6, 7.6, 15.4 Hz, 1 H), 5.85 (dt, J ϭ 1.5, 15.4 Hz, 1 H),
4.17 (q, J ϭ 7.3 Hz, 2 H), 3.81 (q, J ϭ 5.6 Hz, 1 H), 3.73 (d of A night, it was poured into half-saturated NaCl solution (20 mL) and
ϭ
.
1H NMR (400 MHz, CDCl3): δ ϭ 6.91 acetate (196 mg, 0.56 mmol) in CH2Cl2 (2 mL) was added. After
the reaction mixture had been stirred at room temperature over-
3
3
of ABq, J ϭ 4.0, JAB ϭ 11.1 Hz, 1 H), 3.55 (d of B of ABq, J ϭ
extracted with diethyl ether (2 ϫ 50 mL). The combined organic
Eur. J. Org. Chem. 2003, 1733Ϫ1740
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1737

P. Phukan, S. Sasmal, M. E. Maier
FULL PAPER
layers were dried with Na2SO4, filtered, and concentrated. Purifi-
(MgSO4), filtered, and concentrated in vacuo. The crude product
cation of the residue by flash chromatography (EtOAc/petroleum was purified by flash chromatography (10% EtOAc in petroleum
ether, 5:95) gave dienoate 16 as a colorless oil (57 mg, 78%). [α]D25
ϩ66.6 (c ϭ 0.73, CHCl3).
ϭ
ether) to give 471 mg (75%) of alcohol 20 as a colorless oil. [α]D25
Ϫ19.0 (c ϭ 0.72, CHCl3). IR (neat): ν˜ ϭ 3394, 2955, 2930, 2858,
1470, 1254, 1095 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ
ϭ
.
(4R)-4-Benzyl-3-[(2R,3S)-5-{[(tert-butyl)dimethylsilyl]oxy}-3-
hydroxy-2-methylpentanoyl]-1,3-oxazolidin-2-one (18): Titanium()
chloride (0.49 mL, 4.50 mmol) was added dropwise to a cooled (0
°C) solution of the oxazolidinone[24] ent-4 (1.0 g, 4.29 mmol) in
CH2Cl2 (50 mL), and the mixture was stirred for 5 min. Sub-
sequently, (Ϫ)-sparteine (2.51 g, 10.72 mmol) was added to the yel-
low slurry. The dark-red enolate solution was stirred at 0 °C for
20 min, after which aldehyde 17[46] (0.89 g 4.72 mmol), dissolved in
CH2Cl2 (10 mL), was added dropwise. The reaction mixture was
stirred at 0 °C for 1 h and then quenched with half-saturated
NH4Cl (10 mL). After separation of the layers, the organic layer
was dried (Na2SO4), filtered, and concentrated in vacuo. Purifi-
cation of the residue by flash chromatography (20% EtOAc in
3.95Ϫ3.88 (m, 1 H), 3.72Ϫ3.56 (m, 3 H), 3.52 (dd, J ϭ 5.1, 10.6 Hz,
1 H), 2.87 (br. s, 1 H), 2.02Ϫ1.91 (m, 1 H), 1.68 (q, J ϭ 6.31 Hz,
1 H), 0.87 (s, 18 H), 0.78 (d, J ϭ 7.1 Hz, 3 H), 0.08 (s, 3 H), 0.06
(s, 3 H), 0.02 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
72.7, 65.9, 59.8, 39.8, 35.1, 25.8, 18.2, 17.9, 12.5, Ϫ4.8, Ϫ5.3 ppm.
MS (EI): m/z (%) ϭ 305 (10), 289 (3), 261 (4), 189 (14), 173 (100),
147 (70), 133 (33), 115 (27), 105 (40), 89 (96), 73 (93). HRMS (FT-
ICR): calcd. for C18H42O3Si2Na [M ϩ Na]ϩ 385.25647, found
385.25582.
(2S,3S)-3,5-Bis{[(tert-butyl)dimethylsilyl]oxy}-2-methylpentyl
4-Methylbenzenesulfonate (21): p-Toluenesulfonyl chloride (420 mg,
2.2 mmol) was added at 0 °C to a stirred solution of alcohol 20
(400 mg 1.10 mmol) in pyridine (3 mL). After having been stirred
for 2 h, the reaction mixture was quenched by addition of water
(10 mL), diluted with Et2O (50 mL), and washed with 1  HCl,
saturated NaHCO3 solution, and brine. The organic layer was dried
(Na2SO4), filtered, and concentrated. Filtration of the residue
through a short pad of silica gel (5% EtOAc in petroleum ether)
and evaporation of the solvent gave the pure tosylate 21 as a
slightly yellow oil (543 mg, 95%). [α]2D5 ϭ Ϫ15.7 (c ϭ 1.28, CHCl3).
1H NMR (400 MHz, CDCl3): δ ϭ 7.76 (d, J ϭ 8.3 Hz, 2 H), 7.31
(d, J ϭ 7.8 Hz, 2 H), 4.02 (dd, J ϭ 5.8, 9.1 Hz, 1 H), 3.86Ϫ3.75
(m, 2 H), 3.6Ϫ3.47 (m, 2 H), 2.42 (s, 3 H), 1.97Ϫ1.83 (m, 1 H),
1.65Ϫ1.53 (m, 1 H), 1.50Ϫ1.41 (m, 1 H), 0.85 (s, 9 H), 0.77 (s, 9
H), 0.00 (s, 6 H), Ϫ0.01 (s, 3 H), Ϫ0.07 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 144.6, 133.0, 129.7, 127.9, 72.6, 69.2, 59.5,
37.9, 36.4, 25.8, 25.7, 21.6, 18.1, 17.9, 11.1, Ϫ4.5, Ϫ4.9, Ϫ5.4 ppm.
MS (EI), m/z (%) ϭ 459 (2), 361 (19), 345 (6), 303 (6), 287 (7), 271
(3), 229 (100), 213 (53), 173 (32), 133 (15), 91 (30), 73 (60), 57
(10). HRMS (FT-ICR): calcd. for C25H48O5SSi2Na [M ϩ Na]ϩ
539.26532, found 539.26623.
petroleum ether) afforded 1.58 g (87%) of 18, colorless oil. [α]D24
Ϫ42.0 (c ϭ 0.98, CHCl3). IR (neat): ν˜ ϭ 1209, 1241, 1697, 1737,
1782, 2857, 2954, 3504 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ
ϭ
.
7.3Ϫ7.05 (m, 5 H), 4.65Ϫ4.55 (m, 1 H), 4.17Ϫ4.01 (m, 3 H),
3.82Ϫ3.66 (m, 3 H), 3.51 (d, J ϭ 1.8 Hz, 1 H), 3.18 (dd, J ϭ 8.3,
13.1 Hz, 1 H), 2.70 (dd, J ϭ 9.4, 13.4 Hz, 1 H), 1.75Ϫ1.63 (m, 1
H), 1.61Ϫ1.51 (m, 1 H), 1.21 (d, J ϭ 7.1 Hz, 3 H), 0.82 (s, 9 H),
0.17 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 176.2, 152.9,
135.1, 129.3, 128.8, 127.2, 71.0, 65.9, 61.7, 55.2, 42.7, 37.6, 35.8,
25.8, 18.1, 11.2, Ϫ5.6 ppm. MS (EI): m/z (%) ϭ 364 (22), 346 (5),
290 (4), 272 (12), 252 (61), 234 (29), 187 (46), 131 (100), 91 (35),
57 (7). HRMS (FT-ICR): calcd. for C22H35NO5SiNa [M ϩ Na]ϩ
444.21767, found 444.21793.
(4R)-4-Benzyl-3-[(2R,3S)-3,5-bis{[(tert-butyl)dimethylsilyl]oxy}-2-
methylpentanoyl]-1,3-oxazolidin-2-one (19): tert-Butyldimethylsilyl
triflate (0.407 g, 0.35 mL, 1.54 mmol) was added to a solution of
compound 18 (0.50 g, 1.18 mmol) and 2,6-lutidine (0.32 g,
0.34 mL, 2.96 mmol) in CH2Cl2 (10 mL) and the solution was
stirred overnight. Water (5 mL) was added, the mixture was stirred
for 20 min, and the organic layer was separated. The organic phase
was washed with saturated NaHCO3 solution and brine, dried
(Na2SO4), filtered, and concentrated. Flash chromatography of the
residue (10% EtOAc in petroleum ether) afforded silyl ether 19
(0.593 g, 93%) as a colorless, gummy product, which solidified on
standing; m.p. 52Ϫ53 °C. [α]D25 ϭ Ϫ56.5. IR (neat): ν˜ ϭ 1209, 1252,
(3S)-3,5-Bis{[(tert-butyl)dimethylsilyl]oxy}-2-methylpent-1-ene (22)
(a) From Tosylate 21: A mixture of the tosylate 21 (400 mg,
0.81 mmol), NaI (365 mg, 2.44 mmol), and DBU (371 mg,
2.44 mmol) in glyme (10 mL) was heated at reflux with stirring for
3 h. After the reaction mixture had cooled to room temperature,
Et2O (50 mL) and H2O (50 mL) were added and the layers were
separated. The combined organic layers were washed with satu-
rated NaHCO3 solution, 1  HCl, and brine, dried (Na2SO4), fil-
tered, and concentrated. Filtration of the residue through a short
pad of silica gel (petroleum ether) gave the pure alkene 22 (266 mg,
95%) as a colorless oil. [α]2D4 ϭ Ϫ14.2 (c ϭ 0.88, CHCl3) {ref.[47]
[α]2D0 ϭ Ϫ10.0 (c ϭ 1.0, CHCl3)}. IR (neat): ν˜ ϭ 2954, 2930, 2857,
1
1383, 1703, 1784, 2857, 2954 cmϪ1. H NMR (400 MHz, CDCl3):
δ ϭ 7.31Ϫ7.10 (m, 5 H), 4.60Ϫ4.51 (m, 1 H), 4.17Ϫ4.01 (m, 3 H),
3.89Ϫ3.80 (m, 1 H), 3.71Ϫ3.56 (m, 2 H), 3.22 (dd, J ϭ 3.0, 13.4 Hz,
1 H), 2.71 (dd, J ϭ 9.6, 13.4 Hz, 1 H), 1.88Ϫ1.68 (m, 2 H), 1.18
(d, J ϭ 6.8 Hz, 3 H), 0.84 (s, 18 H), 0.02, 0.00, 0.00, Ϫ0.03 (4 s, 12
H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 175.1, 152.9, 135.3,
129.4, 128.9, 127.3, 70.4, 65.9, 59.4, 55.6, 43.1, 38.2, 37.6, 25.9,
18.2, 17.9, 12.3, Ϫ4.5, Ϫ4.9, Ϫ5.4 ppm. MS (EI): m/z (%) ϭ 478
(9), 422 (6), 346 (3), 290 (11), 234 (14), 171 (7), 117 (8), 91 (8), 84
(100), 73 (24). HRMS (FT-ICR): calcd. for C28H49NO5Si2Na [M
ϩ Na]ϩ 558.30415, found 558.30402.
1
1471, 1254, 1092 cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 4.85 (s,
1 H), 4.74 (s, 1 H), 4.20 (dd, J ϭ 5.3, 7.3 Hz, 1 H), 3.68Ϫ3.55 (m,
2 H), 1.17Ϫ1.57 (m, 5 H), 0.88 (s, 18 H), 0.03 (s, 9 H), Ϫ0.01 (s, 3
H) ppm. 13C NMR (100 MHz CDCl3): δ ϭ 147.8, 110.4, 73.4, 59.7,
39.5, 25.8, 18.2, 17.1, Ϫ4.8, Ϫ5.2, Ϫ5.3 ppm. MS (EI): m/z (%) ϭ
287 (48), 259 (72), 219 (24), 189 (67), 147 (100), 133 (24), 73 (58).
(2S,3S)-3,5-Bis{[(tert-butyl)dimethylsilyl]oxy}-2-methylpentan-1-ol
(20): A solution of NaBH4 (261 mg, 6.9 mmol) in H2O (3 mL) was
added at 0 °C to a stirred solution of 19 (925 mg, 1.72 mmol) in
(b) From Ketone 33: nBuLi (1.00 mL, 2.5  in hexane, 2.5 mmol)
THF (15 mL). The reaction mixture was stirred at 0 °C for 5 min was added dropwise at 0 °C to a stirred suspension of (methyl)tri-
and then at room temperature for 2 h. The reaction was quenched
by addition of saturated aqueous NH4Cl solution and the mixture
was stirred for 1 h, after which it was extracted with EtOAc (2 ϫ
20 mL). The combined organic layers were washed with saturated
NaHCO3 solution (20 mL), H2O (20 mL), and brine (20 mL), dried
phenylphosphonium bromide (1.10 g, 3.08 mmol) in THF (10 mL).
The resulting red ylide solution was stirred at 0 °C for 30 min, after
which a solution of ketone 33 (500 mg, 1.44 mmol) in THF (5 mL)
was added dropwise at 0 °C over 10 min. The cooling bath was
removed and the reaction mixture was stirred at ambient tempera-
1738
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1733Ϫ1740

Flexible Routes to the 5-Hydroxy Acid Fragment of the Cryptophycins
FULL PAPER
ture for 48 h. Et2O (20 mL) and H2O (20 mL) were added, and the
layers were separated. The aqueous phase was extracted with Et2O
(2 ϫ 10 mL) and the combined organic extracts were washed with
brine, dried (Na2SO4), filtered, and concentrated. Flash chromatog-
raphy of the residue (petroleum ether) gave the olefin 22 (237 mg,
48%) as a colorless oil. [α]2D5 ϭ Ϫ13.5 (c ϭ 1.09, CHCl3).
(EtOAc/petroleum ether, 1:9) gave 200 mg (76%) of 25 as a white
gum. [α]2D5 ϭ Ϫ1.93 (c ϭ 0.66, CHCl3). IR (film): ν˜ ϭ 2954, 2930,
1
1497, 1343, 1255, 1153, 1096 cmϪl. H NMR (400 MHz, CDCl3):
δ ϭ 7.71Ϫ7.64 (m, 2 H), 7.63Ϫ7.54 (m, 3 H), 3.95 (dd, J ϭ 2.8,
14.9 Hz, 1 H), 3.89Ϫ3.83 (m, 1 H), 3.64 (t, J ϭ 6.2 Hz, 2 H), 3.44
(dd, J ϭ 9.1, 14.91 Hz, 1 H), 2.48Ϫ2.38 (m, 2 H), 1.77Ϫ1.53 (m, 2
H), 1.19 (d, J ϭ 6.8 Hz, 3 H), 0.87, 0.86 (2 s, 18 H), 0.06, 0.04,
0.03, 0.02 (4 s, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
154.0, 133.1, 131.4, 129.7, 125.1, 72.5, 59.25, 58.0, 36.8, 32.6, 25.9,
18.2, 18.0, 17.0, Ϫ4.4, Ϫ4.7, Ϫ5.5 ppm. MS (EI): m/z (%) ϭ 498
(3), 439 (2), 249 (8), 189 (13), 175 (28), 147 (53), 117 (84), 84 (89),
49 (100). HRMS (FT-ICR): calcd. for C25H46N4O4SSi2Na [M ϩ
Na]ϩ 577.26705, found 577.26660.
(2R,3S)-3,5-Bis{[(tert-butyl)dimethylsilyl]oxy}-2-methyl-1-pentanol
(23): A solution of 9-BBN in THF (0.5 , 4.3 mL, 2.17 mmol) was
added dropwise at 0 °C to a solution of alkene 22 (250 mg,
0.72 mmol) in THF (2 mL). After the addition, the mixture was
stirred at ambient temperature for 3 h and was then treated with
EtOH (1.35 mL), aqueous NaOH (3 , 0.9 mL), and 30% aqueous
H2O2 (0.9 mL) and stirred at room temperature for 2 h. The mix-
ture was saturated with solid K2CO3 and extracted with Et2O. The {(1E,3R,4S)-4,6-Bis{[(tert-butyl)dimethylsilyl]oxy}-3-methylhex-1-
combined organic layers were washed with brine, dried (Na2SO4),
filtered, and concentrated. Purification of the residue by flash chro-
enyl}benzene (26): Potassium bis(trimethylsilyl)amide (1 mL, 0.5 
in toluene, 0.5 mmol) was added dropwise at Ϫ55 °C to a solution
matography (10% EtOAc in petroleum ether) gave alcohol 22 of sulfone 25 (185 mg, 0.33 mmol) in dry DME (3 mL). The re-
(218 mg, 83%) as a colorless oil. [α]2D5 ϭ Ϫ4.0 (c ϭ 0.89, CHCl3).
IR (neat): ν˜ ϭ 3394, 2955, 2930, 2858, 1470, 1254, 1095, 1036 cmϪ1
1H NMR (400 MHz, CDCl3): δ ϭ 3.86 (dd, J ϭ 6.1, 10.1 Hz, 1
sulting bright yellow-orange solution was stirred at the same tem-
perature for 40 min, after which freshly distilled benzaldehyde
(46 mg, 0.43 mmol) in DME (1 mL) was added dropwise. The reac-
.
H), 3.73 (dd, J ϭ 4.3, 10.9 Hz, 1 H), 3.62 (t, J ϭ 6.6 Hz, 2 H), 3.49 tion mixture was stirred at the same temperature for 1 h and then
(dd, J ϭ 5.3, 10.9 Hz, 1 H), 2.68 (br. s, 1 H), 1.90Ϫ1.79 (m, 0.5 allowed to warm to 0 °C over 1 h. After stirring at room tempera-
H), 1.78Ϫ1.69 (m, 2 H), 1.56Ϫ1.45 (m, 0.5 H), 0.98 (d, J ϭ 7.1 Hz, ture for 2 h, the reaction mixture was partitioned between H2O
3 H), 0.85, 0.86 (2 s, 18 H), 0.05, 0.00 (2 s, 12 H) ppm. 13C NMR and Et2O, the phases were separated, and the aqueous phase was
(100 MHz, CDCl3): δ ϭ 74.2, 65.2, 56.7, 38.5, 37.5, 25.8, 18.2, 18.0, extracted with Et2O. The combined organic layers were washed
14.3, 4.5, Ϫ4.7, Ϫ5.4 ppm. MS (EI), m/z (%) ϭ 305 (8), 289 (2),
261 (3), 189 (13), 173 (100), 147 (70), 133 (34), 115 (27), 105 (40),
with water and brine, dried (Na2SO4), filtered, and concentrated.
The residue was purified by flash chromatography (EtOAc/petro-
89 (98), 73 (93). HRMS (FT-ICR): calcd. for C18H42O3Si2Na [M leum ether, 5:95) to provide the styrene 26 (102 mg, 70%) as a color-
ϩ Na]ϩ 385.25647, found 385.25613.
less oil. [α]D25 ϭ ϩ17.8 (c ϭ 1.00, CHCl3) {ref.[18] [α]2D2 ϭ ϩ24.6 (c ϭ
1.84, CHCl3); ref.[17] [α]D20 ϭ ϩ23 (c ϭ 0.77, CHCl3)}. IR (film):
ν˜ ϭ 2955, 2928, 1471, 1463, 1256, 1097 cmϪl. 1H NMR (400 MHz,
CDCl3): δ ϭ 7.30Ϫ7.05 (m, 5 H), 6.26 (d, J ϭ 15.9 Hz, 1 H), 6.07
(dd, J ϭ 7.8, 15.9 Hz, 1 H), 3.79Ϫ3.67 (m, 1 H), 3.65Ϫ3.47 (m, 2
H), 2.45Ϫ2.31 (m, 1 H), 1.56 (q, J ϭ 6.6 Hz, 2 H), 1.01 (d, J ϭ
6.8 Hz, 3 H), 0.82, 0.79 (2 s, 18 H), 0.02, Ϫ0.06 (2 s, 12 H) ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 137.8, 132.8, 129.8, 128.4,
126.9, 126.0, 72.7, 60.2, 42.7, 36.7, 25.9, 18.3, 18.1, 15.5, Ϫ4.5,
Ϫ5.3 ppm. MS (EI): m/z (%) ϭ 323 (3), 303 (14), 261 (20), 189
(30), 173 (9), 147 (100), 131 (22), 115 (14), 89 (38), 73 (58).
5-{[(2S,3S)-3,5-Bis{[(tert-butyl)dimethylsilyl]oxy}-2-methylpentyl]-
sulfanyl}-1-phenyl-1H-tetrazole (24): A premixed solution of 1-phe-
nyl-1H-tetrazole-5-thiol (167 mg, 0.94 mmol) and diisopropyl azo-
dicarboxylate (190 mg, 0.94 mmol) in DMF (3.5 mL) was added to
a solution of alcohol 23 (210 mg, 0.58 mmol) and triphenylphos-
phane (246 mg, 0.94 mmol) in DMF (2.5 mL) at 0 °C. The reaction
mixture was stirred at room temperature for 30 min, after which
water (10 mL) and Et2O (10 mL) were added. The layers were sepa-
rated, and the aqueous layer was extracted with Et2O. The com-
bined organic layers were washed with water, dried (Na2SO4), fil-
tered, and concentrated. Flash chromatography of the residue (5% (3S,4R,5E)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4-methyl-6-phenyl-5-
EtOAc in petroleum ether) gave the sulfide 24 (255 mg, 84%) as a hexen-1-ol (27): A mixture of pyridinium toluene-4-sulfonate
colorless oil. [α]2D5 ϭ ϩ0.48 (c ϭ 0.92, CHCl3). IR (neat): ν˜ ϭ 2954,
(17 mg, 0.067 mmol) and silyl ether 26 (100 mg, 0.23 mmol) was
1H NMR stirred at 50 °C in methanol (5 mL) for 4 h. Most of the methanol
(400 MHz, CDCl3): δ ϭ 7.63Ϫ7.43 (m, 5 H), 3.99Ϫ3.81 (m, 1 H), was then removed under reduced pressure and the mixture was par-
2930, 2857, 1500, 1469, 1387, 1253, 1093 cmϪ1
.
3.79Ϫ3.60 (m, 2 H), 3.51 (dd, J ϭ 5.3, 13.1 Hz, 1 H), 3.17 (dd, J ϭ
8.1, 12.9 Hz, 1 H), 2.19Ϫ2.02 (m, 1 H), 1.76Ϫ1.54 (m, 2 H), 1.04
titioned between H2O and Et2O. The aqueous layer was extracted
with Et2O and the combined organic layers were washed with satu-
(d, J ϭ 6.8 Hz, 3 H), 0.86 (s, 18 H), 0.05, 0.04, 0.01, 0.00 (4 s, 12 rated NaHCO3 solution and brine, dried (Na2SO4), filtered, and
H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 154.7, 133.8, 130.0,
129.7, 123.8, 71.8, 59.6, 37.7, 36.1, 36.0, 25.9, 18.0, 15.3, Ϫ4.5,
concentrated. Purification of the residue by flash chromatography
(EtOAc/petroleum ether, 1:9) gave the alcohol 27 (63 mg, 86%) as
Ϫ4.6, Ϫ5.4 ppm. MS (EI): m/z (%) ϭ 466 (2), 277 (7), 235 (10), a colorless oil. [α]2D5 ϭ ϩ44.4 (c ϭ 0.75, CHCl3) {ref.[18] [α]2D2
ϭ
213 (36), 173 (30), 147 (64), 133 (28), 89 (97), 73 (100). HRMS ϩ28.8 (c ϭ 2.59, CHCl3); ref.[17] [α]D20 ϭ ϩ28.3 (c ϭ 0.675,
(FT-ICR): calcd. for C25H46N4O2SSi2Na [M ϩ Na]ϩ 545.27722, CHCl3)}. IR (film): ν˜ ϭ 3352, 2955, 2929, 1469, 1376, 1254, 1093
found 545.27773.
cmϪl 1H NMR (400 MHz, CDCl3): δ ϭ 7.31Ϫ7.02 (m, 5 H),
.
6.36Ϫ6.19 (m, 1 H), 6.12Ϫ5.91 (m, 1 H), 3.87Ϫ3.72 (m, 1 H),
3.70Ϫ3.53 (m, 2 H), 2.53Ϫ2.36 (m, 1 H), 1.88 (br. s, 1 H), 1.62 (q,
J ϭ 6.3 Hz, 2 H), 0.99 (d, J ϭ 6.8 Hz, 3 H), 0.80 (s, 18 H), 0.00,
Ϫ0.02 (2 s, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 137.5,
132.6, 130.0, 128.5, 127.0, 126.0, 74.6, 60.5, 42.7, 34.9, 25.9, 18.0,
14.8, Ϫ4.46, Ϫ4.6 ppm. MS (EI): m/z (%) ϭ 263 (2), 189 (78), 147
(41), 91 (27), 89 (90), 75 (100), 73 (80).
5-{[(2S,3S)-3,5-Bis{[(tert-butyl)dimethylsilyl]oxy}-2-methylpentyl]-
sulfonyl}-1-phenyl-1H-tetrazole (25): A solution of the sulfide 24
(250 mg, 0.48 mmol) in CH2Cl2 (10 mL), cooled to 0 °C, was
treated with mCPBA (247 mg, 1.43 mmol), followed by stirring at
room temperature for 3 h. The reaction mixture was treated with
10% aqueous sodium sulfite solution (20 mL), diluted with CH2Cl2
(30 mL), and washed with saturated aqueous NaHCO3 (2 ϫ
30 mL). The organic layer was dried (Na2SO4), filtered, and con-
centrated. Purification of the residue by flash chromatography
(3S)-3-{[(tert-Butyl)dimethylsilyl]oxy}dihydrofuran-2(3H)-one
(32):[39] Imidazole (2.2 g, 32.32 mmol) and TBSCl (2.44 g,
Eur. J. Org. Chem. 2003, 1733Ϫ1740
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1739

P. Phukan, S. Sasmal, M. E. Maier
FULL PAPER
[11]
[12]
[13]
[14]
16.16 mmol) were added to a solution of lactone 31[39] (1.5 g,
14.7 mmol) in DMF (10 mL). The mixture was stirred for 24 h at
room temperature. Subsequently, the reaction was quenched with
saturated NaHCO3 solution and the mixture was extracted with
Et2O. The ethereal layer was washed with saturated NaCl solution,
dried (Na2SO4), filtered, and concentrated. Flash chromatography
(EtOAc/petroleum ether, 1:9) afforded silyl ether 32 (2.95 g, 92%)
as a colorless oil. [α]2D5 ϭ ϩ31.9 (c ϭ 0.92, CHCl3). IR (film): ν˜ ϭ
2931, 2859, 1790, 1473, 1362, 1254, 1154, 1022, 840, 781 cmϪ1. 1H
NMR (400 MHz, CDCl3): δ ϭ 4.43Ϫ4.31 (m, 2 H), 4.22Ϫ4.12 (m,
1 H), 2.49Ϫ2.39 (m, 1 H), 2.26Ϫ2.16 (m, 1 H), 0.89 (s, 9 H), 0.15
(s, 3 H), 0.12 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
175.9, 68.2, 64.7, 32.3, 25.6, 18.2, 4.8, 5.3 ppm.
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(3S)-3,5-Bis[tert-butyl(dimethyl)silyloxy]pentan-2-one (33):[39] MeLi
(1.6 mL, 2.56 mmol, 1.6  solution in Et2O) was added dropwise
at Ϫ78 °C to a stirred solution of silyl ether 32 (500 mg, 2.3 mmol)
in THF (10 mL). After having been stirred at Ϫ78 °C for 3 h, the
reaction mixture was quenched by the addition of glacial acetic
acid (0.17 mL, 2.97 mmol). Et2O (40 mL) and saturated aqueous
NaHCO3 solution (20 mL) were added. The organic layer was sepa-
rated after stirring for 5 min, and the aqueous layer was extracted
with Et2O (2 ϫ 30 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated to give crude (3S)-3-{[(tert-
butyl)dimethylsilyl]oxy}-2-methyltetrahydrofuran-2-ol. The crude
hydroxy ketone was dissolved in DMF (3 mL), imidazole (313 mg,
4.6 mmol) and TBSCl (350 mg, 2.32 mmol) were added, and the
mixture was stirred at room temperature for 24 h. The mixture was
partitioned between Et2O (40 mL) and water (40 mL). The organic
layer was washed with water and brine, dried (Na2SO4), filtered,
and concentrated. Purification of the residue by flash chromatogra-
phy (EtOAc/petroleum ether, 5:95) afforded ketone 33 (516 mg,
65%) as a colorless oil. IR (neat): ν˜ ϭ 2957, 2859, 1720, 1473, 1361,
1256, 1106, 838, 778 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 4.13
(dd, J ϭ 5.3, 6.8 Hz, 1 H), 3.74Ϫ3.60 (m, 2 H), 2.13 (s, 3 H),
1.86Ϫ1.69 (m, 2 H), 0.89, 0.85 (2 s, 18 H), 0.03, 0.01, 0.00 (3 s, 12
H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 211.83, 75.71, 58.33,
37.75, 25.87, 25.69, 25.34, 18.24, 18.08, Ϫ5.02, Ϫ5.48 ppm.
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Received December 11, 2002
1740
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1733Ϫ1740