A practical building block for the synthesis of discodermolide

Article abstract of DOI:10.1021/op049950l

A new highly diastereoselective and practical route to the lactone 6a which is used as a key building block for the total synthesis of the microtubule-stabilizing anticancer agent discodermolide is reported. This exploits the chiral auxiliary (4R)-4-isopr

Full text of DOI:10.1021/op049950l

Organic Process Research & Development 2004, 8, 597−602
A Practical Building Block for the Synthesis of Discodermolide
Olivier Loiseleur,* Guido Koch,† and Trixie Wagner‡
NoVartis Pharma AG, Process R&D, CH-4002 Basel, Switzerland
Abstract:
A new highly diastereoselective and practical route to the
lactone 6a which is used as a key building block for the total
synthesis of the microtubule-stabilizing anticancer agent dis-
codermolide is reported. This exploits the chiral auxiliary (4R)-
4-isopropyl-5,5-diphenyloxazolidin-2-one (7) which conveys
crystallinity to the synthetic intermediates throughout the entire
process. Purifications can thus be performed by recrystalliza-
tion, avoiding chromatography to afford the final product in
Figure 1.
high enantiomeric purity. The overall efficiency is augmented
by the facile recovery of the auxiliary by precipitation at the
end of the sequence.
the scarce supply of the material available from the natural
source. The yield initially reported by Gunasekara in the
isolation of discodermolide was 0.002% (w/w from frozen
sponge). The supply problem has since been alleviated by
recent progress in the total synthesis of discodermolide4
which has culminated in the preparation of 1 g of material
by Smith and co-workers4d,e and the report by Paterson and
co-workers of two generations of practical syntheses.4k,m,n
Accordingly, discodermolide is currently undergoing Phase
I clinical trials sponsored by Novartis Pharma AG who
licensed the compound from the Harbor Branch Oceano-
graphic Institution in 1998 to develop it as an anticancer
agent. Drug supply needs (60 g) have been met using total
synthesis.4p However, to address the drug supply of more
advanced clinical trials, further efforts in synthesis are
necessary. Our interest for the development of a process for
discodermolide revolved first around the efficient access to
the recurring anti-syn stereochemical triad highlighted in
Figure 1. The use of a common building block containing
this motif results in a significant reduction of complexity in
the total synthesis of discodermolide by diminishing the total
number of steps.4c
Introduction
Discodermolide (1) is a marine polyketide discovered by
Gunasekara and co-workers at the Harbor Branch Oceano-
graphic Institution in 1990 and is isolated from a rare
caribbean deep-sea sponge Discodermia dissoluta.1 Disco-
dermolide is now recognized as a member of a group of
antimitotic agents including Taxol (paclitaxel), known to act
by microtubule stabilization.2 The highly encouraging bio-
logical profile of discodermolide makes it a promising
candidate for clinical development as a chemotherapeutic
agent in oncology.3 However, extensive exploration of the
efficacy of this compound has initially been hampered by
* Present mailing address: Syngenta AG, Crop Protection Research &
Technology, Lead Finding Unit, WRO-1060.5.04, CH-4001 Basel, Switzerland.
Telephone: +41 61 323 70 91. Fax: +41 61 323 87 26. E-mail: olivier.
loiseleur@syngenta.com.
† Present mailing address: Novartis Pharma AG, NIBR Basel, Combinatorial
Chemistry Unit, WSJ-507.704, 4002 Basel, Switzerland. Telephone: +41 61
324 42 38. Fax: +41 61 324 42 36. E-mail: guido.koch@pharma.novartis.com.
‡ Present mailing address: Novartis Pharma AG, NIBR Basel, Analytical &
Imaging Sciences, WSJ-503.12.08, CH-4002 Basel, Switzerland. Telephone: +41
61 324 6042. Fax: +41 61 324 5930. E-mail: trixie.wagner@pharma.novartis.com.
(1) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K. J. Org.
Chem. 1990, 55, 4912 (Correction: J. Org. Chem. 1991, 56, 1346).
Gunasekera, S. P.; Pomponi, S. A.; Longley, R. E. U.S. Patent No. 5840750
US, November 24, 1998. Gunasekera, S. P.; Paul, G. K.; Longley, R. E.;
Isbrucker, R. A.; Pomponi, S. A. J. Nat. Prod. 2002, 65, 1643.
(4) (a) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L. J. Am.
Chem. Soc. 1993, 115, 12621. (b) Nerenberg, J. B.; Hung, D. T.; Schreiber,
S. L. J. Am. Chem. Soc. 1996, 118, 11054. (c) Smith, A. B., III; Qiu, Y. P.;
Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011. (d) Smith,
A. B., III; Kaufman, M. D.; Beauchamp, T. J.; LaMarche, M. J.; Arimoto,
H. Org. Lett. 1999, 1, 1823. (e) Smith, A. B., III; Beauchamp, T. J.;
LaMarche, M. J.; Kaufman, M. D.; Qiu, Y. P.; Arimoto, H.; Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654. (f) Yang, G.; Myles, D.
C. Tetrahedron Lett. 1994, 35, 1313. (g) Yang, G.; Myles, D. C. Tetrahedron
Lett. 1994, 35, 2503. (h) Harried, S. S.; Yang, G.; Strawn, M. A.; Myles,
D. C. J. Org. Chem. 1997, 62, 6098. (i) Marshall, J. A.; Lu, Z. H.; Johns,
B. A. J. Org. Chem. 1998, 63, 817. (j) Marshall, J. A.; Johns, B. A. J. Org.
Chem. 1998, 63, 7885. (k) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott,
J. P. Angew. Chem., Int. Ed. 2000, 39, 377. (l) Paterson, I.; Florence, G. J.
Tetrahedron Lett. 2000, 41, 6935. (m) Paterson, I.; Florence, G. J.; Gerlach,
K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535. (n) Paterson,
I.; Delgado, O.; Florence, G. J.; Lyothier, I.; Scott, J. P.; Sereinig, N. Org.
Lett. 2003, 5, 35. (o) Halstead, P. D. Ph.D. Thesis, Harvard University,
Cambridge, 1998. (p) Mickel, S. J.; Niederer, D.; Daeffler, R.; Osmani, A.;
Kuesters, E.; Schmid, E.; Schaer, K.; Gamboni, R.; Chen, Weichun, L. E.;
Kinder, F. R., Jr.; Konigsberger, K.; Prasad, K.; Ramsey, T. M.; Repic, O.;
Wang, R.-M.; Florence, G.; Lyothier, I.; Paterson, I. Org. Process Res. DeV.
2004, 8, 122 and references therein.
(2) Paterson, I.; Florence, G. J. Eur. J. Org. Chem. 2003, 2193.
(3) ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M.; Longley, R. E.;
Gunasekera, S. P.; Rosenkranz, H. S.; Day, B. W. Biochemistry 1996, 35,
243. Balachandran, R.; ter Haar, E.; Welsh, M. J.; Grant, S. G.; Day, B. W.
Anti-Cancer Drugs 1998, 9, 67. Kowalski, R. J.; Giannakakou, P.;
Gunasekera, S. P.; Longley, R. E.; Day, B. W.; Hamel, E. Mol. Pharmacol.
1997, 52, 613. Martello, L. A.; McDaid, H. M.; Regl, D. L.; Yang, C. H.;
Meng, D.; Pettus, T. R. R.; Kaufman, M. D.; Arimoto, H.; Danishefsky, S.
J.; Smith, A. B., III; Horwitz, S. B. Clin. Cancer Res. 2000, 6, 1978. Kinder,
F. R.; Bair, K. W.; Chen, W. C.; Florence, G. J.; Francavilla, C.; Geng, P.;
Gunasekera, S.; Lassota, P. T.; Longley, R. E.; Palermo, M. G.; Paterson,
I.; Pomponi, S.; Ramsey, T. M.; Rogers, L.; Sabio, M.; Sereinig, N.;
Sorenson, E.; Wang, R. M.; Wright, A.; Guo, Q. Abstracts of Papers of the
American Chemical Society, 224, 236-MEDI, part 2, American Chemical
Society, Washington, August 18, 2002, 13, 1161. Honore, S.; Kamath, K.;
Braguer, D.; Wilson, L.; Briand, C.; Jordan, M. A. Mol. Cancer Ther. 2003,
2, 1303.
10.1021/op049950l CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/26/2004
Vol. 8, No. 4, 2004 / Organic Process Research & Development
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597

Scheme 1a
a (a) nBu2BOTf (1 equiv), Et3N (1.2 equiv), methacrolein (3 equiv), CH2Cl2, -78 °C to 0 °C, 2 h. (b) TBDMSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 0.5 h, 70% over two
steps. (c) (i) 9-BBN (2 equiv), THF, 23 °C, 5 h; (ii) pH 7, H2O2, EtOH/THF, 23 °C, 15 h, 86%. (d) KO-t-Bu (2 mol %), THF, 0 °C, 1 h, quantitative.
Results and Discussion
reaction mixture. Hence, a simple filtration provided analyti-
cally pure lactone 6a. The overall yield for the discoder-
molide common building block was 60% (based on 2).
Whereas this synthesis of 6a provided us with a proof of
concept, demonstrating the high crystallinity of all the
oxazolidinone-containing intermediates as well as the ease
of recycling of the auxiliary and supplied us with an initial
multigram amount of material to pursue on our synthesis of
discodermolide, it was associated with a number of problems.
The range of the protecting group for the C3-OH function
that could be introduced at the stage of the derivative 3 was
somewhat limited. Specifically, PMB was installed with
moderate yield, even by using p-methoxybenzyl-trichloro-
acetimidate (PMBOC(dNH)CCl3) and a series of acid
catalysts. More importantly, the TES-protected lactone 6b
(Scheme 2), a variation needed downstream in the synthesis,
could not be accessed through our route. Indeed, the TES
group when installed after the boron aldol underwent partial
cleavage during the hydroboration step. Furthermore, 9-BBN
caused difficulties as the 1,5-cyclooctanediol resulting from
oxidative workup precluded the crystallization of the solid
alcohol 5a and a chromatography was required for purifica-
tion.
To address these obstacles and gain in flexibility for
alternative protecting groups, we modified our route as shown
in Scheme 2. The aldol product 3 was hydroborated directly
prior to silylation. Whereas disiamylborane as an alternative
to 9-BBN proved ineffective in terms of conversion and BH3‚
DMS resulted in partial cleavage of the auxiliary during
reaction, thexylborane, which is converted to volatile 2,3-
dimethyl-butane-2-ol after oxidative workup, allowed direct
crystallization of the diol 8 in 84% yield from the reaction
mixture thus avoiding chromatographic purification. Thexyl-
borane showed the same diastereoselectivity as 9-BBN, and
only the desired anti-diastereomer could be observed in the
hydroboration. Strong chelation of boric acid by the diol 8
caused problems in the purification step at the beginning,
but this could be circumvented by treatment of the crude
diol 8 prior to recrystallization with aqueous NaOH, at pH
< 11 to avoid spontaneous lactonization to 6c.
We selected the known lactone 6a containing the correct
triad of contiguous stereocenters present in discodermolide
as our common building block.5 The critical role of this
common fragment required development of a route amenable
to large-scale production.6 Whereas syntheses of 6a are
reported, their adaptation to a production process remains
problematic in terms of length and chromatographic purifica-
tions.7 To control stereochemistry, we chose as point of
departure the Evans syn-boron aldol protocol enlisting the
inexpensive methacrolein and the known acylated oxazoli-
dinone 2 (Scheme 1).8a,b We anticipated that the presence of
the second generation auxiliary (4R)-4-isopropyl-5,5-diphen-
yloxazolidin-2-one (7) developed by Seebach would confer
high crystallinity to the intermediates throughout the route
toward 6a thus providing a practical advantage for isolation
and purifications.9
Aldol coupling followed by TBDMS-silylation gave the
crystalline intermediate 4 as a single diastereomer in 70%
yield over two steps. Hydroboration of the alkene moiety in
4 with 9-BBN then afforded the expected anti-product 5a
as a single diastereomer.10 Finally, lactonization, best per-
formed by treatment of 5a with a catalytic amount of
t-BuOK, provided 6a as a solid in quantitative yield. Isolation
of 6a was facilitated by removal of the recyclable oxazoli-
dinone auxiliary through quantitative crystallization from the
(5) Koch, G.; Loiseleur, O. Patent No. 0257251 WO, July 25, 2002.
(6) A related approach has been reported independently by Day and co-workers:
Day, B. W.; Kangani, C. O.; Avor, K. S. Tetrahedron: Asymmetry 2002,
13, 1161.
(7) (a) Paterson, I.; Patel, S. K.; Porter, J. R. Tetrahedron Lett. 1983, 24, 3395.
(b) Seebach, D.; Chow, H.-F.; Jackson, R. F. W.; Sutter, M. A.; Thaisrivongs,
S.; Zimmermann, J. Liebigs Ann. Chem. 1986, 1281.
(8) (a) Hintermann, T.; Seebach, D. HelV. Chim. Acta 1998, 81, 2093. (b)
Brenner, M.; La Vecchia, L.; Leutert, Th.; Seebach, D. Org. Synth. 2003,
80, 57. (c) Gibson, C. L.; Gillon, K.; Cook, S. Tetrahedron Lett. 1998, 39,
6733.
(9) The propensity of 7 and its enantiomer to give crystalline derivatives has
been reported independently by Hintermann and Seebach and Gibson and
co-worker.8a,c For a convenient preparation of 7, see ref 8b. Both enantiomers
of the auxiliary are commercially available (Aldrich, Shiratori Pharmaceu-
ticals Co. Ltd., Japan and Onyx Scientific Ltd. UK).
(10) Still, W. C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105, 2487. Evans, D.
A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am. Chem. Soc. 1995, 117,
3448.
598
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Scheme 2a
a (a) Bu2-BOTf (1 equiv), Et3N (1.3 equiv), methacrolein (3 equiv), CH2Cl2, -78 °C to 0 °C, 2 h, 74%. (b) (i) thexylborane (1.7 equiv), 0 °C, 2 h; (ii) pH 7, H2O2,
EtOH/THF, 23 °C, 14 h, 84%. (c) 9a: TBDMSOTf (2.1 equiv), 2,6-lutidine (2.5 equiv), 0 °C, 2.0 h. 9b: TESCl (2.1 equiv), imidazole (2.4 equiv), DMAP (10 mol
%), DMF, 40 °C, 2 h. (d) 5a: Cl2CCO2H, MeOH, 0 °C, 1.75 h. 5b: AcOH, THF/MeOH/H2O 5:5:1, 0 °C, 5 h, 72% over two steps. (e) KO-t-Bu (2 mol %), THF, 0
°C, 0.5 h. 6a: 88% over three steps. 6b: 95%.
the lactone to the lactol 10 as a mixture of anomers (ca. 4:1)
by DIBAL-H reduction and intended to take advantage of
the masked aldehyde to install the trisubstituted C13-C14
double bond present in discodermolide (Figure 1) via a Still-
Gennari olefination (Scheme 3, 11).11
However, 10 proved to be unreactive to the standard
reaction conditions. The direct conversion of the lactone to
the olefin by using a protocol developed by Takacs and co-
workers was unsuccessful as well.12 Standard Wittig condi-
tions used in a test reaction did provide olefination product,
but this was accompanied by extensive R,â-elimination of
silanol to give 12. Likewise, attempted conversion of 6a to
the TBDMS- or acetate-protected hydroxyaldehyde only
Figure 2. Structure of 8 in the crystal.14 Atomic displacement
ellipsoids drawn at the 50% probability level, hydrogen atoms
resulted in silylation or acetylation of the anomeric hydroxyl
group to give 13a and 13b. With the lactol proving to be
drawn as spheres of arbitrary radius. Stereochemistry: C18R,
reluctant to undergo ring-opening,13 we turned our attention
C24R, C26S, C28S. Flack x refined to 0.01(11).
on the reactivity of the lactone and found that it could
reproducibly be converted to the corresponding Weinreb
amide 14 providing a convenient starting point for further
synthetic elaboration (Scheme 4).
Silylation of 8 with TBDMSOTf followed by deprotection
of the primary hydroxyl group and lactonization provided
6a in 55% overall yield (based on 2). The TES-lactone 6b
was obtained in 43% overall yield. Both 6a and 6b were
purified by distillation under high vacuum. Potential spon-
Conclusion
In conclusion, we have reported the practical preparation
of the lactone 6a chosen as a common building block for
taneous lactonization upon shelf storage of alcohols 8, 5a,
and 5b to give respectively 6c, 6a, and 6b was precluded
the synthesis of discodermolide, a promising anti-cancer drug
by the fact that these compounds are crystalline. These
candidate currently in Phase I clinical trials. We have chosen
efficient five-step sequences can be performed routinely on
a strategy which makes use of the easily recyclable oxazo-
a 100 g scale without any chromatography. In contrast to
lidinone 7 to control stereochemistry efficiently, to impart
the approaches adopted by other groups,4 the synthesis of
our common building block does not make use of the
crystallinity to the intermediates throughout the process, and
to avoid the costly Roche ester. The elaboration of 6a to
expensive methyl (S)-2-methyl-3-hydroxypropionate (Roche
key fragments of discodermolide and their coupling is
ester) as a starting material. The stereochemistry is dictated
presently subject to a patent application and will be reported
by the readily recovered oxazolidinone 7 instead, which
in due course.
augments the efficiency of the procedure. The configurations
of 6a and 6b were confirmed by single-crystal X-ray
Experimental Section
diffraction of the precursor 8 (Figure 2) as well as by
(R)-3-[(2R,3R)-3-Hydroxy-2,4-dimethyl-pent-4-enoyl]-
comparison of the analytical data of 6a with a sample of
4-isopropyl-5,5-diphenyl-oxazolidin-2-one (3). A solution
lactone prepared in our lab according to a published
procedure.7a
(11) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(12) Takacs, J. M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett. 1986, 27, 1257.
(13) An indirect solution for a similar case has since been reported by Tholander
Ring-opening of 6a as the initial step for further elabora-
tions toward the key fragments necessary for the synthesis
of discodermolide was investigated next. We first converted
and Carreira: Tholander, J.; Carreira, E. M. HelV. Chim. Acta 2001, 84,
613.
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599

Scheme 3a
a (a) DIBAL-H, THF, -78°, 96%. (b) DIBAL-H, (CF3CH2O)P(O)CH(CH3)CO2Et, KHMDS, 18-crown-6, THF. (c) (CF3CH2O)P(O)CH(CH3)CO2Et, KHMDS,
18-crown-6, THF. (d) [(C6H5)3PCH(CH3)CO2Et]+Br-, BuLi, THF. (e) TBDMSOTf, Et3N, CH2Cl2. (f) TBDMSCL, imidazole, DMAP, DMF. (g) Ac2O, pyridine,
DMAP.
Scheme 4a
126.8, 113.4, 90.4, 77.2, 66.3, 43.2, 31.4, 23.3, 19.0, 17.6,
17.1; IR (KBr) νmax 3512m, 2966m, 1768s, 1687s, 1451m,
1363s, 1320m, 1209s, 1182m, 1052m, 994m, 949m, 910m,
761m, 705m cm-1; MS (ES+) m/z (%) 837 (34, [2 M +
Na]+), 631 (100, [3 M + Ca]2+), 623 (100, [2 M + Na +
H]2+), 430 (65, [M + Na]+).
(R)-3-[(2R,3S,4S)-3,5-Dihydroxy-2,4-dimethyl-pentanoyl]-
4-isopropyl-5,5-diphenyl-oxazolidin-2-one (8). A solution
of thexyl borane in THF [prepared in situ by dropwise
addition at 0 °C of 2,3-dimethyl-2-butene (37.2 g, 442 mmol)
to BH3‚THF (1 M in THF, 442 mL, 442 mmol) followed by
1 h stirring at 0 °C] at 0 °C under an atmosphere of argon
was treated dropwise over a period of 40 min with a solution
of 3 (106 g, 260 mmol) in THF (100 mL). After stirring at
0 °C for 2 h, the reaction mixture was treated sequentially
and under temperature control (ca. 0 °C) with EtOH/THF
1:1 v/v (520 mL) over a period of 25 min, pH 7 phosphate
buffer (520 mL) over a period of 15 min, and 35% aqueous
hydrogen peroxide (250 mL) over a period of 20 min.
Thereupon, the resulting solution was stirred successively
at 0 °C for 1 h and at 23 °C for 14 h before being extracted
twice with hexane (1500 mL and 1000 mL). The organic
extracts were washed with Na2S2O3 (1000 mL and 600 mL)
and pH 7 phosphate buffer (600 mL), combined, dried
(MgSO4), and concentrated in vacuo. The residue was
dissolved in a mixture of CH2Cl2 (1000 mL) and H2O (600
mL), and the pH of the water layer of the resultant two-
phase mixture was increased from 4.1 to 11.2 by dropwise
addition monitored with a pH meter over a period of 1 h of
1 N NaOH (110 mL). After, the pH of the aqueous layer
remained stable at 11.2 for 15 min, the layers were separated.
The aqueous layer was extracted with CH2Cl2 (250 mL). The
organic extracts were washed with saturated aqueous NH4-
Cl (300 mL) and saturated aqueous NaCl (300 mL),
combined, dried (MgSO4), and concentrated in vacuo to give
the crude diol (109.2 g) as colorless crystals. Purification
by recrystallization in methylcyclohexane (1.3 L) afforded
92.8 g (84%) of diol 8 as colorless crystals: mp 103.5-
a (a) iPrMgCl (3 equiv), HN(OMe)Me‚HCl (1.6 equiv), THF, -15 °C, 1.5 h,
98%.
of 2 (20.2 g, 60 mmol) in 80 mL of CH2Cl2 under an
atmosphere of argon was treated sequentially at 0 °C with a
1.0 M solution of n-Bu2BOTf in CH2Cl2 (60 mL, 60 mmol)
and triethylamine (7.6 g, 75 mmol). After stirring at 0 °C
for 1 h, the resulting solution was cooled to -78 °C.
Methacrolein (12.6 g, 180 mmol) dissolved in 20 mL of CH2-
Cl2 was then added. The reaction mixture was stirred
successively at -78 °C for 1 h and at -45 °C for 1 h. Water
(80 mL) was added at 0 °C. The phases were separated, and
the organic layer was treated sequentially at 0 °C with
phosphate buffer (pH 7, 80 mL) and 35% H2O2 (10 mL).
After stirring for 30 min at ambient temperature, the layers
were separated. The organic layer was washed with 10%
aqueous Na2S2O3 (2 × 80 mL) and brine (80 mL), dried
over MgSO4, and concentrated in vacuo to give 34.2 g of
the crude alcohol 3 as a slightly yellowish crystalline
material. Purification by recrystallization in heptane afforded
18.1 g (74%) of product as colorless crystals: mp 99.5-
1
100.0 °C; Rf ) 0.27 (SiO2, 3:1 heptane-AcOEt); H NMR
(DMSO-d6, 400 MHz, 300 K) δ 7.62 (d, J ) 8.4 Hz, 2H,
C5-(C6H5)2), 7.56 (d, J ) 7.6 Hz, 2H, C5-(C6H5)2), 7.45-
7.28 (two m, 6H, C5-(C6H5)2), 6.91 (d, J ) 2.8 Hz, 1H,
C4-H), 4.93 (d, J ) 5.6 Hz, 1H, C3-OH), 4.32 (s, 1H, C5-
Ha), 4.03 (q, J ) 1.6 Hz, 1H, C5-Hb), 3.85 (dd, J ) 9.2, 5.2
Hz, 1H, C3-H), 3.78 (qd, J ) 9.2, 6.4 Hz, 1H, C2-H), 2.05
(qqd, J ) 7.2, 6.8, 2.8 Hz, 1H, C4-CH(CH3)2), 1.22 (d, J )
6.4 Hz, 3H, C2-CH3), 1.17 (s, 3H, C4-CH3), 0.88 (d, J )
7.2 Hz, 3H, C4-CH(CH3)2), 0.64 (d, J ) 6.8 Hz, 3H, C4-
CH(CH3)2); 13C NMR (CD3OD, 125 MHz, 300 K): δ 176.1,
154.3, 147.4, 145.0, 140.1, 130.6, 130.3, 130.1, 129.7, 127.2,
600
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1
104.5 °C; Rf ) 0.27 (SiO2, 1:1 heptane-AcOEt); H NMR
(R)-3-[(2R,3S,4S)-3-(tert-Butyl-dimethyl-silanyloxy)-5-
hydroxy-2,4-dimethyl-pentanoyl]-4-isopropyl-5,5-diphen-
yl-oxazolidin-2-one (5a). To a solution of crude 9a (40 g)
in MeOH (100 mL) at 0 °C was added dichloroacetic acid
(38 g, 295 mmol). After stirring at 0 °C for 1 h and 45 min,
the reaction mixture was quenched with saturated aqueous
NaHCO3 (600 mL) and extracted with TBME (2 × 400 mL).
The organic extracts were washed with saturated aqueous
NaCl (400 mL), combined, dried (MgSO4), and concentrated
in vacuo to provide the alcohol 5a (39 g) as a colorless solid.
This material was used in the next step without further
purification. Rf ) 0.59 (SiO2, 1:1 heptane-AcOEt); 1H NMR
(DMSO, 500 MHz, 300 K) δ 7.66 (d, J ) 7.8 Hz, 2H, C5-
(C6H5)2), 7.58 (d, J ) 7.8 Hz, 2H, C5-(C6H5)2), 7.42-7.20
(two m, 6H, C5-(C6H5)2), 5.57 (d, J ) 2.2 Hz, 1H, C4-H),
3.93 (t, J ) 4.9 Hz, 1H, C5-OH), 3.89 (dd, J ) 6.0, 3.9 Hz,
1H, C3-H), 3.71 (qd, J ) 6.9, 6.0 Hz, 1H, C2-H), 2.98-
2.94 (m, 1H, C5-Ha), 2.70-2.66 (m, 1H, C5-Hb), 2.12-
2.02 (br m, 1H, C4-CH(CH3)2), 1.44-1.34 (br m, 1H, C4-
H), 1.13 (d, J ) 6.9 Hz, 3H, C2-CH3), 0.86 (d, J ) 6.8 Hz,
3H, C4-CH(CH3)2), 0.83 (s, 9H, SiC(CH3)3), 0.61 (d, J )
6.7 Hz, 3H, C4-CH(CH3)2), 0.49 (d, J ) 7.0 Hz, 3H, C4-
CH3), -0.05 (s, 3H, SiCH3), -0.10 (s, 3H, SiCH3); 13C NMR
(DMSO-d6, 125 MHz, 300 K) δ 174.7, 152.2, 143.1, 138.2,
128.8, 128.5, 128.3, 127.8, 125.3, 124.8, 88.5, 73.0, 64.6,
62.6, 42.1, 40.1, 29.7, 25.9, 21.3, 18.0, 15.52, 15.44, 12.9,
-4.2, -4.4; IR (KBr) νmax 3437s, 2961m, 2931m, 1787s,
1690m, 1451m, 1384m, 1362m, 1252m, 1207m, 1178m,
1082m, 1052m, 991m, 838m, 705m cm-1; MS (ES+) m/z
(%) 1101 (42, [2 M + Na]+), 829 (12, [3 M + Ca]2+), 562
(100, [M + Na]+), 522 (28, [MH - H2O]+).
(3R,4S,5S)-4-(tert-Butyldimethylsilanyloxy)-3,5-dimethyl-
tetrahydro-pyran-2-one (6a). To a solution of crude 5a (39
g) in THF (220 mL) at 0 °C under an atmosphere of argon
was added a solution of t-BuOK (1 M in THF, 1.2 mL, 1.2
mmol). The resulting reaction mixture was stirred for 30 min
at 0 °C, whereas cleaved oxazolidinone precipitated gradually
as a colorless solid. THF was removed under reduced
pressure, and the residue was taken in heptane (500 mL).
After stirring for 30 min at 0 °C, the resulting suspension
was filtrated and the residue was washed with heptane (250
mL) (14.5 g of pure oxazolidinone 7 was isolated by this
process). The filtrate was collected and concentrated in vacuo
to give the crude lactone. Purification by Kugelrohr distil-
lation (200 °C, 0.065 mbar) afforded 13.4 g (88% over three
steps) of pure product 6a as a colorless crystalline solid: mp
53-54 °C; Rf ) 0.49 (SiO2, 1:1 heptane-AcOEt); 1H NMR
(DMSO-d6, 500 MHz, 300 K) δ 4.18 (dd, J ) 10.8, 4.6 Hz,
1H, C6-Ha), 4.05 (dd, J ) 10.8, 8.7 Hz, 1H, C6-Hb), 3.82
(dd, J ) 5.1, 2.9 Hz, 1H, C4-H), 2.45 (qd, J ) 7.5, 5.1 Hz,
1H, C3-H), 2.21 (dqdd, J ) 8.7, 6.9, 4.6, 2.9 Hz, 1H, C5-
H), 1. 19 (d, J ) 7.5 Hz, 3H, C3-CH3), 0.89 (d, J ) 6.9
Hz, 3H, C5-CH3), 0.87 (s, 9H, SiC(CH3)3), 0.072 (s, 3H,
SiCH3), 0.067 (s, 3H, SiCH3); 13C NMR (DMSO-d6, 125
MHz, 300 K): δ 172.9, 72.5, 69.7, 42.7, 30.0, 25.6, 17.7,
15.2, 11.3, -4.79, -4.81; IR (KBr) νmax 2958m, 2928m,
2855m, 1727s, 1473m, 1257m, 1207m, 1126m, 1113m,
1049s, 1018m, 996m, 853s, 837s, 778s cm-1; MS (ES+)
(DMSO, 400 MHz, 300 K) δ 7.61 (d, J ) 7.6 Hz, 2H, C5-
(C6H5)2), 7.55 (d, J ) 7.5 Hz, 2H, C5-(C6H5)2), 7.48-7.20
(m, 6H, C5-(C6H5)2), 5.53 (d, J ) 2.5 Hz, 1H, C4-H), 4.38
(d, J ) 6.8 Hz, 1H, C3-OH), 4.14 (t, J ) 4.8 Hz, 1H, C5-
OH), 3.63 (dq, J ) 7.2, 6.8 Hz, 1H, C2-H), 3.35-3.25 (ddd,
1H, C3-H, partially obscured by water), 3.11-3.06 (m, 1H,
C5-Ha), 3.00-2.95 (m, 1H, C5-Hb), 2.10-1.98 (br qqd, J
) 6.9, 6.7, 2.5 Hz, 1H, C4-CH(CH3)2), 1.14 (d, J ) 6.8
Hz, 3H, C2-CH3), 1.10-0.98 (br m, 1H, C4-H), 0.86 (d, J
) 6.9 Hz, 3H, C4-CH(CH3)2), 0.62 (d, J ) 6.7 Hz, 3H,
C4-CH(CH3)2), 0.45 (d, J ) 6.9 Hz, 3H, C4-CH3); 13C
NMR (CDCL3, 75 MHz, 300 K): δ 175.1, 152.5, 143.1,
138.2, 128.79, 128.76, 128.54, 128.51, 128.3, 127.8, 125.4,
125.3, 124.98, 124.95, 88.7, 73.6, 64.5, 63.2, 41.1, 39.0, 29.6,
21.4, 15.7, 14.6, 14.0; IR (KBr) νmax 3460m (br), 2966m,
1776s, 1707m, 1452m, 1362m, 1320w, 1245w, 1210m,
1178m, 1150w, 1052m, 1037m, 991m, 762m, 706m cm-1;
MS (ES+) m/z (%) 873 (28, [2 M + Na]+), 658 (12, [3 M
+ Ca]2+), 448 (100, [M + Na]+), 445 (13, [2 M + Ca]2+).
(R)-3-[(2R,3S,4S)-3,5-Bis(tert-butyl-dimethyl-silanyloxy)-
2,4-dimethyl-pentanoyl]-4-isopropyl-5,5-diphenyl-oxazo-
lidin-2-one (9a). To a solution of 8 (25.0 g, 59 mmol) and
2,6-lutidine (17 mL, 146 mmol) in CH2Cl2 (120 mL) at 0
°C under an atmosphere of argon TBDMSOTf (29 mL, 126
mmol) was added dropwise over a period of 10 min. After
stirring at 0 °C for 2 h, the reaction mixture was worked up.
Aqueous 1 N HCl (150 mL) was added dropwise at 0 °C
over a period of 10 min followed by heptane (200 mL). The
aqueous layer was extracted with heptane (100 mL). The
organic extracts were combined, washed with saturated
aqueous NaHCO3 (200 mL) and saturated aqueous NaCl (200
mL), dried over MgSO4, and concentrated in vacuo to give
40 g of the crude bis-silyl ether 9a as a colorless solid which
did not require further purification. An analytical sample of
9a was obtained by recrystallization in MeOH: colorless
crystals; mp 104-105 °C; Rf ) 0.66 (SiO2, 1:1 heptane-
1
AcOEt); H NMR (DMSO, 400 MHz, 300 K) δ 7.67 (d, J
) 8.0 Hz, 2H, C5-(C6H5)2), 7.58 (d, J ) 7.9 Hz, 2H, C5-
(C6H5)2), 7.42-7.20 (two m, 6H, C5-(C6H5)2), 5.60 (d, J )
1.9 Hz, 1H, C4-H), 3.90 (dd, J ) 5.8, 4.0 Hz, 1H, C3-H),
3.73 (qd, J ) 6.9, 5.8 Hz, 1H, C2-H), 3.19 (dd, J ) 9.9,
6.5 Hz, 1H, C5-Ha), 3.03 (dd, J ) 9.9, 6.7 Hz, 1H, C5-
Hb), 2.08 (heptd, J ) 6.7, 1.9 Hz, 1H, C4-CH(CH3)2), 1.41
(qddd, J ) 7.0, 6.7, 6.5, 4.0 Hz, 1H, C4-H), 1.15 (d, J )
6.9 Hz, 3H, C2-CH3), 0.87 (d, J ) 6.7 Hz, 3H, C4-CH-
(CH3)2), 0.83 (s, 9H, SiC(CH3)3), 0.80 (s, 9H, SiC(CH3)3),
0.61 (d, J ) 6.7 Hz, 3H, C4-CH(CH3)2), 0.56 (d, J ) 7.0
Hz, 3H, C4-CH3), -0.04 (s, 3H, SiCH3), -0.09 (s, 3H,
SiCH3), -0.11 (s, 3H, SiCH3), -0.14 (s, 3H, SiCH3); 13C
NMR (CDCl3, 75 MHz, 300 K) δ 175.5, 151.9, 142.0, 137.8,
128.5, 128.1, 127.9, 127.4, 125.4, 125.0, 88.5, 73.2, 64.2,
64.1, 41.9, 41.1, 29.6, 25.6, 25.5, 21.4, 17.9, 17.8, 15.8, 15.4,
13.5, -4.4, -4.6, -5.9; IR (KBr) νmax 2954m, 2928m,
1772s, 1712m, 1450m, 1363m, 1251m, 1209m, 1093m,
1055m, 861m, 838m, 776m, 759m, 704m cm-1; MS (ES+)
m/z (%) 1000 (7, [3 M + Ca]2+), 676 (100, [M + Na]+),
673 (14, [2 M + Ca]2+), 654 (8, [M + H]+).
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601

m/z (%) 539 (30, [M + 2 Na]+), 322 (55, [M + CH3CN]+),
281 (100, [M + Na]+).
Å, V ) 2234.4(5) Å3, Z ) 4, Dc ) 1.265 g‚cm-3, 61 492
reflections measured, 4070 independent (Rint ) 0.0375), 3.95°
< θ < 68.24°, 404 parameters, 0 restraints, R1 ) 0.0244,
wR2 ) 0.0604 for 3989 reflections with I > 2σ(I), R1 )
0.0251, wR2 ) 0.0610 for all 4070 data, GoF ) 1.049, Flack
x ) 0.01(11), res. el. dens. ) +0.17/-0.19 e‚Å3. Diffraction
data were collected at 100 K with a Bruker AXS SMART
6000 CCD detector on a three-circle platform goniometer
with Cu KR radiation from a fine-focus sealed tube generator
equipped with a graphite monochromator. A semiempirical
absorption correction was applied, based on the intensities
of symmetry-related reflections measured at different angular
settings.15 The structure was solved and refined on F2 with
the SHELXTL suite of programs.16 Non-hydrogen atoms
were refined with anisotropic displacement parameters; all
hydrogen atoms could be located in DF maps and were
refined isotropically.
(2R,3S,4S)-3-(tert-Butyldimethylsilanyloxy)-5-hydroxy-
2,4-dimethyl-pentanoic Acid Methoxy-methyl-amide (14).
A solution of 6a (1.80 g, 6.96 mmol) in THF (23 mL) at 23
°C under an atmosphere of argon was treated with N,O-
dimethylhydroxylamine hydrochloride (1.05 g, 10.79 mmol),
and the resulting suspension was cooled at -15 °C. A
solution of isopropylmagnesium chloride in THF (2 M, 10.5
mL, 20.9 mmol) was added dropwise over a period of 40
min (exothermic), whereas the reaction mixture became a
clear gray-colored solution which was further stirred between
-15 °C and -10 °C for 1 h and 20 min before being worked
up by dilution with TBME (20 mL) followed by addition of
a 1:1 v/v mixture of saturated aqueous NH4Cl and water (40
mL). The mixture was allowed to warm up at 23 °C and
was stirred until the salts had dissolved. The layers were
separated, and the aqueous layer was extracted with TBME
(15 mL). The organic extracts were washed with saturated
aqueous NaCl (3 × 25 mL), combined, dried (MgSO4), and
concentrated in vacuo to give the crude alcohol 14 (2.18 g,
98%) as colorless crystals which did not require further
purification: mp 28.9-29.8 °C; Rf ) 0.18 (SiO2, 1:1
Acknowledgment
D. Grimler is gratefully acknowledged for the preparation
of a large quantity of (4R)-4-isopropyl-5,5-diphenyloxazo-
lidinone 7. We express our gratitude to F. Schuerch for the
preparation of a substantial amount of 3. The experimental
work of V. Christen and A. Hirni are gratefully acknowl-
edged. We thank the analytical department of the Novartis
Institutes for BioMedical Research Basel for their support.
1
heptane-AcOEt); H NMR (DMSO, 500 MHz, 300 K) δ
4.29 (dd, J ) 5.1, 4.7. Hz, 1H, C5-OH), 3.87 (dd, J ) 5.5,
5.2 Hz, 1H, C3-H), 3.67 (s, 3H, N-OCH3), 3.46 (m, 1H,
C5-Ha), 3.16-3.07 (m, 1H, C5-Hb, partially obscured by
N-CH3), 3.07 (s, 3H, N-CH3), 3.08-2.97 (br m, 1H, C2-
H, partially obscured by N-CH3), 1.70-1.59 (br m, 1H, C4-
H), 0.99 (d, J ) 6.9 Hz, 3H, C2-CH3), 0.89 (d, J ) 7.0 Hz,
3H, C4-CH3), 0.88 (s, 9H, SiC(CH3)3), 0.04 (s, 3H, SiCH3),
-0.01 (s, 3H, SiCH3); 13C NMR (DMSO-d6, 125 MHz, 300
K) 175.3, 74.7, 62.5, 61.1, 41.0, 37.9, 31.8, 26.0, 18.1, 14.1,
13.4, -4.1, -4.2; IR (film) νmax 3450m, 2956s, 2938s,
2885m, 2857m, 1634m, 1463m, 1386m, 1255s, 1102m,
1073m, 1050m, 1004m, 869m, 837s, 775s cm-1; MS (ES+)
m/z (%) 661 (40, [2 M + Na]+), 499 (23, [3 M + Ca]2+),
491 (8, [3 M + Na + H]2+), 342 (100, [M + Na]+), 320
(57, [M + H]+).
Supporting Information Available
Detailed descriptions of experimental procedures for the
synthesis of 6a (according to Scheme 1), 6b, and 10 with
analytical data. Crystallographic data (excluding structure
factors) have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication number
CCDC 228658.
Received for review March 9, 2004.
OP049950L
(14) Spek, A. L. PLATON, a Multi-Purpose Crystallographic Tool; Utrecht
University: Utrecht, The Netherlands (http://www.cryst.chem.uu.nl/platon).
(15) Sheldrick, G. M. SADABS, version 2.10; University of Go¨ttingen: Go¨ttingen,
Germany, 1999.
(16) Sheldrick, G. M. SHELXTL, version 6.12; Bruker AXS Inc.: Madison, WI,
2003.
Crystal Structure Analysis of 8: Crystals suitable for
diffraction experiments grown from CH2Cl2/hexane. C25H31-
NO5, Mr ) 425.51, orthorhombic, space group P212121 (No.
19) with a ) 8.414(1) Å, b ) 13.760(2) Å, c ) 19.299(2)
602
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