Enantioselective synthesis of iclaprim enantiomers- A versatile approach to 2-substituted chiral chromenes

Article abstract of DOI:10.1021/jo100566c

Figure presented Both enantiomers of the DHFR inhibitor iclaprim (R)-1 and (S)-1 were synthesized from the cyclopropyl homoallyl alcohols (R)-6 and (S)-6, respectively. As key steps these transformations include a Mitsunobu reaction and the formation of the diaminopyrimidine unit prior to a novel cyclization procedure to obtain the desired chromene heterocycle. The moderate enantioselectivity of the products (R)-1 and (S)-1 is related to the Mitsunobu reaction, which unfortunately did not proceed with complete inversion of configuration.

Full text of DOI:10.1021/jo100566c

pubs.acs.org/joc
Enantioselective Synthesis of Iclaprim Enantiomers;A Versatile
Approach to 2-Substituted Chiral Chromenes
,†
Chouaib Tahtaoui,* Arnold Demailly, Carole Guidemann, Cecile Joyeux, and
†
†
‡
ꢀ
Peter Schneider*,†,
†ARPIDA AG, Duggingerstrasse 23, 4153 Reinach, Switzerland, and ‡Laboratoire de Chimie Organique,
Bioorganique et Macromoleꢀculaire, Ecole Nationale Supeꢀrieure de Chimie de Mulhouse,
3 rue Alfred Werner, 68093 Mulhouse, France. Present address: Ki Consulting Ltd., Postfach 821,
CH-4153 Reinach BL, Switzerland
chouaib@hotmail.com; peter.schneider@intergga.ch
Received March 25, 2010
Both enantiomers of the DHFR inhibitor iclaprim (R)-1 and (S)-1 were synthesized from the
cyclopropyl homoallyl alcohols (R)-6 and (S)-6, respectively. As key steps these transformations
include a Mitsunobu reaction and the formation of the diaminopyrimidine unit prior to a novel
cyclization procedure to obtain the desired chromene heterocycle. The moderate enantioselectivity of
the products (R)-1 and (S)-1 is related to the Mitsunobu reaction, which unfortunately did not
proceed with complete inversion of configuration.
Introduction
ARPIDA AG developed iclaprim 1 (Figure 1) as a race-
mate for complicated skin and skin structure infections
(cSSSI) caused by Gram-positive organisms, especially
methicillin-resistant (MRSA) and TMP-resistant Staphylo-
coccus aureus. This chromene-benzyldiaminopyrimidine
shows submicromolar activities against pathogenic micro-
organisms such as Staphylococci, Enterobacter, Neisseria,
Pneumocystis carinii, Streptococcus pneumoniae, and Hae-
mophilus influenza. Both enantiomers of iclaprim exhibit
similar activity against the DHFR enzymes of S. aureus
and a similar antimicrobial profile against a broad range of
bacteria.4
Iclaprim and trimethoprim are diaminopyrimidine deri-
vatives which are active against a broad panel of bacteria.1
Trimethoprim (TMP) is successfully used in combination
with sulfamethoxazole in the sequential blockade of the de
novo synthesis of tetrahydrofolic acid to treat bacterial
infections. Since the discovery of trimethoprim in 1965 many
companies have initiated programs to synthesize derivatives
within the benzyldiaminopyrimidine series to improve physi-
cochemical and pharmacological profiles.1,2 As a result of
these activities several new inhibitors of dihydrofolate re-
ductase (DHFR) have recently progressed into clinical de-
velopment due to their potent anticancer or antibiotic
properties.1,3
*To whom correspondence should be addressed. Phone: þ33(0)389446830/
þ41 76 308 7363. Fax: þ41 61 421 8781.
(1) Kompis, I. M.; Islam, K.; Then, R. L. Chem. Rev. 2005, 105, 593–620.
(2) Masciadri, R. U.S. Patent 5,773,446; Hoffmann-La Roche, June 30,
1998.
(3) Schneider, P.; Hawser, S.; Islam, K. Bioorg. Med. Chem. Lett. 2003,
13, 4217–4221.
FIGURE 1. Enantiomers of iclaprim.
DOI: 10.1021/jo100566c
r
Published on Web 05/06/2010
J. Org. Chem. 2010, 75, 3781–3785 3781
2010 American Chemical Society

Tahtaoui et al.
JOCArticle
SCHEME 1. Retrosynthesis Leading to Iclaprim Enantiomer (S)-1
Chromenes (2H-1benzopyran derivatives) have been
widely identified as important core-structures in many nat-
ural products and in many bioactive compounds.5-7 Wipf
et al.7 have developed a seven step synthesis of a 2-cyclopro-
pylchromene with a 59% enantiomeric excess (ee), which
could serve as an intermediate for the preparation of (S)-1.
However, the synthesis was not completed to obtain iclaprim
enantiomer (S)-1 because the elevated reaction conditions to
generate the diaminopyrimidine moiety would have race-
mized the product. Indeed, racemization of chiral chromenes
is known to be induced by light7,8 or by heat.9 Chromenes
have been obtained by ring-closing olefin metathesis7,10 or
through chroman-4-ones and subsequent reduction of the
ketone and elimination of water.11,12
SCHEME 2. Enzymatic Resolution of Racemic 6
TABLE 1. Lipase-Catalyzed Resolution of 6
enantiomeric
excess (ee)
lipasea from
product
(R)-6
yield (%)
Herein, we wish to report various approaches to chiral
cyclopropyl allyl methanols as intermediates for the synthe-
sis of both iclaprim enantiomers, (R)-1 and (S)-1.
Candida cylindracea
35
60
43%
12%
(S)-6
Results and Discussion
Pseudomonas
cepacia
Our strategy is outlined in Scheme 1 using the cyclization
of the chiral intermediate (R)-2 to obtain the desired chiral
iclaprim enantiomer (S)-1. To prevent racemization, the
diaminopyrimidine moiety had to be generated before this
cyclization in three steps starting from chiral ether (R)-4,
which could be obtained by a Mitsunobu reaction between
phenol 5 and the chiral homoallylic alcohol (S)-6.
To prepare both enantiomers of iclaprim an efficient synthe-
sis of the homoallylic alcohols (S)-6 and (R)-6 was required.
For the purpose we pursued an enzymatic resolution of racemic
6, which was easily available from aldehyde 7 (Scheme 2).13
Several lipases14 were investigated for their efficiency
in the presence of vinyl acetate: Amano Lipase PS from
(R)-6
(S)-6
50
47
58%
91%
a50 mg lipase/mmol of 6.
TABLE 2. Enantiomeric Excess of Products at Various Ratios of
Substrate 6 to Lipase from Pseudomonas cepacia
entry mg of lipase per mmol 6 products enantiomeric excess (ee)
1
2
3
4
35
35
50
50
100
100
250
250
(R)-6
(S)-6
(R)-6
(S)-6
(R)-6
(S)-6
(R)-6
(S)-6
48%
90%
58%
91%
72%
64%
78%
39%
(4) Hartmann, P. G.; Kompis, I. M.; Jaeger, J.; Mukhija, S.; Islam, K.
Abstracts, F2020, 42nd Interscience Conference on Antimicrobial Agents
and Chemotherapy, San Diego, CA, Sept 27-30, 2002; American Society for
Microbiology: Washington, DC, 2002.
Pseudomonas cepacia, Amano Lipase from Pseudomonas
fluorescens, lipase from Candida cylindracea, Amano Lipase
M from Mucor javanicus, Amano Lipase A from Aspergillus
niger, and Amano Lipase G from Penicillium camemberti.
Among these enzymes, only the lipases from Pseudomonas
cepacia and from Candida cylindracea displayed an enzy-
matic resolution (Table 1). The best enantioselectivity was
accomplished by using the Amano lipase PS from Pseudo-
monas cepacia. The homoallylic alcohol (S)-6 was obtained
in 91% ee and the (R)-6 in 58% ee after hydrolysis of the
acetate (R)-6-Ac (Table 1). Several attempts to improve the
ee values for both enantiomers by changing the ratio of
substrate/enzyme proved to be unsuccessful (Table 2).
Accordingly, the lipase-catalyzed resolution of 6 at a
strictly defined substrate/enzyme ratio gave (S)-6 with a high
(5) Kazuo, M.; Kazuya, O.; Hironobu, H. J. Org. Chem. 1989, 54, 557–
560.
(6) Ishikawa, T. Heterocycles 2000, 53, 453–473.
(7) Wipf, P.; Weiner, W. S. J. Org. Chem. 1999, 64, 5321–5324.
(8) (a) Oliveira, M. M.; Moustrou, C.; Carvalho, L. M.; Silva, J. A. C.;
Samat, A.; Guglielmetti, R.; Dubest, R.; Aubard, J.; Oliveira-Campos, A. M.
F. Tetrahedron 2002, 58, 1709–1718. (b) Hardouin, C.; Burgaud, L.; Valleix,
A.; Doris, E. Tetrahedron Lett. 2003, 44, 435–437.
ꢀ
(9) Goujon, J.-Y.; Zammatio, F.; Chretien, J.-M.; Beaudet, I. Tetrahe-
dron 2004, 60, 4037–4049.
(10) Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864–866.
(11) Hodgetts, K. J. Tetrahedron 2005, 61, 6860–6870.
(12) Kawasaki, M.; Kakuda, H.; Goto, M.; Kawabata, S.; Kometani, T.
Tetrahedron: Asymmetry 2003, 14, 1529–1534.
(13) Varadarajan, S.; Mohapatra, D. K.; Datta, A. Tetrahedron Lett.
1998, 39, 1075–1078.
(14) (a) Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996,
52, 3769–3826. (b) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113,
6129–6139. (c) Wang, Y.-F.; Lalonde, J. J.; Momongan, M.; Bergbreiter,
D. A.; Wong, C.-H. J. Am. Chem. Soc. 1988, 110, 7200–7205.
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SCHEME 3. Asymmetric Allylboration of 7
SCHEME 5. Mitsunobu Reactions of 5 with Homoallyl Alcohols
SCHEME 4. Synthesis of (R)-6 from Commercially Available
Diol (S)-8
observed with (S)-6, resulting in ether (R)-4. The stabiliza-
tion properties of a cyclopropyl ring,19 which causes the
Mitsunobu’s phosphonium salt intermediate to have signifi-
cant carbocation character, triggers a mixed SN2/SN1 reac-
tion leading to partially racemized products. Several solvents
like toluene, THF, or dichloromethane were examined in this
reaction of which THF was found to be superior.
In contrast, a control reaction under the same conditions
with the homoallyl alcohol (R)-13 and 5 gave (S)-14 with
complete inversion of configuration (Scheme 5). Several
attempts to improve the Mitsunobu coupling20 conditions
for enantiomers (R)-6 and (S)-6 with 5 failed; hence we had to
accept the loss of ee during this transformation.
91% ee value; however, the value for (R)-6 remained at
modest 58% ee (Table 2, entry 2). We therefore tried the
enantioselective allylation of 7 by means of B-allyldiisopi-
nocampheylborane ((þ)-Ipc2B-allyl),15 but also under these
conditions the homoallylic alcohol (R)-6 was obtained in
only 76% ee (Scheme 3).
The synthesis was then continued for both enantiomers
(R)-4 and (S)-4; the transformations of (S)-4 are shown in
Scheme 6. Reduction of the methyl ester (S)-4 led to the
aldehyde (S)-15 in 91% yield. Constructing the diaminopyr-
imidine heterocycle was done in two steps2 leading to (S)-3.
As oxidation of the double bond at this stage led to complete
decomposition, the amino groups at the diaminopyrimidine
were protected to yield (S)-16 in 70% over three steps.
Subsequently the terminal double bond of (S)-16 was
oxidized with potassium osmate and sodium periodate. Since
purification of the resulting aldehyde (S)-17 induced a retro
1,4-addition the oxidation product was directly cyclized to
the chromene system (R)-18 in the presence of TFA anhy-
dride/TFA in 65% yield. In our hands this new method
proved to be superior over the cyclization to 4-hydroxychro-
manes mediated by ZnCl2.21
The final deprotection of the diaminopyrimidine moiety
was pursued under the mildest conditions available in order
to prevent racemization of the chiral center. Throughout this
synthesis, the ee of intermediates remained constant within
experimental error and iclaprim enantiomer (R)-1 was ob-
tained in 70% ee and 27% overall yield starting from 5. The
corresponding reactions with (R)-4 (55% ee) led to iclaprim
enantiomer (S)-1 (50% ee).
Alternatively to the enzymatic resolution of 6 and the
direct allylation of 7, which gave (R)-6 with only modest ee
values, we developed a synthesis of (R)-6 starting from the
commercially available chiral diol (S)-8 (98% ee). Com-
pound (S)-8 could be made following the enzymatic reduc-
tion of cyclopropyl-oxo-acetic acid.16 Selective protection
gave the monotosylate (S)-9, which was subsequently sily-
lated to furnish (S)-10 in 54% yield over two steps. Exchange
of the tosyl group for iodide gave (S)-11, which was con-
verted to the protected homoallyl alcohol (R)-12 in 73%
yield.17 Finally the TBDMS protecting group was removed
to yield (R)-6 in 31% yield over five steps. The absolute
configuration at C1 of (R)-6 was confirmed according to
Mosher’s method18 and the enantiomeric excess was deter-
mined by GC of the alcohol (R)-6 being 98% ee in agreement
with the value of the starting material (S)-8.
As predicted, the synthesis of the iclaprim enantiomer
(R)-1 was continued with (R)-6 (98% ee, prepared as shown
in Scheme 4). The Mitsunobu coupling of (R)-6 with phenol 5
gave the desired ether (S)-4 in 73% yield, however, with only
72% ee. Loss of enantiopurity during this reaction was also
Conclusions
(15) (a) Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.;
Racherla, U. S. J. Am. Chem. Soc. 1990, 112, 2389–2392. (b) Ramachandran,
P. V. Aldrichim. Acta 2002, 35, 23–35.
In conclusion, this synthesis of the iclaprim enantiomers
(R)-1 and (S)-1 includes three methods to obtain the key
intermediates (R)-6 and (S)-6 in good to excellent enantio-
meric excess and a new approach to chromenes through an
intramolecular, acid-catalyzed cyclization of an aldehyde
(16) Kim, M. J.; Kim, J. Y. J. Chem. Soc., Chem. Commun. 1991, 5, 326–7.
(17) Kutner, A.; Martynow, J.; Chodynski, M.; Szelejewski, W.; Fitak,
H.; Krup, M. WO 03/087048 A2, Instytut Farmaceutyczny, October 23,
2003.
(18) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
(19) (a) Olah, G. A.; Prakash Reddy, V.; Surya Prakash, G. K. Chem.
Rev. 1992, 92, 69–95. (b) Olah, G. A.; Surya Prakash, G. K.; Rasul, G. J. Am.
Chem. Soc. 2008, 130, 9168–9172. (c) Choi, E. T.; Kang, K. H.; Lee, M. H.;
Park, Y. S. Bull. Korean Chem. Soc. 2008, 29, 859–862.
(20) Shintou, T.; Mukaiyama, T. J. Am. Chem. Soc. 2004, 126, 7359–67.
(21) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 9074–9075.
J. Org. Chem. Vol. 75, No. 11, 2010 3783

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SCHEME 6. Completing the Synthesis of Iclaprim Enantiomer (R)-1
with an electron-rich aromatic ring. Unfortunately, the Mit-
sunobu reaction between the phenol 5 and the cyclopropyl
homoallyl alcohols (R)-6 and (S)-6 led to moderate racemized
products; nevertheless iclaprim enantiomers (R)-1 and (S)-1
were obtained in 70% ee and 50% ee, respectively.
(CDCl3, 100 MHz) δ 166.6, 153.2, 151.6, 144.1, 134.2, 124.8,
117.2, 112.2, 106.8, 83.6, 60.8, 56.1, 52.1, 39.4, 14.9, 3.6, 2.1.
LCMS ESIþ (method A) not ionizing. Retention time (Rt): 2.70
min. UV: 233, 265 nm. Chiral HPLC: method 1, 72% ee. HRMS:
[M þ Na]þ calcd for C17H22O5 329.1359, obsd 329.1352.
3-((S)-1-Cyclopropylbut-3-enyloxy)-4,5-dimethoxybenzaldehyde,
(S)-15. Red-Al (70% in toluene, 1 mL, 3.52 mmol, 3 equiv)
in toluene (5 mL) was cooled to 0 °C under N2. Morpholine
(0.194 mL, 2.23 mmol, 1.9 equiv) was added dropwise and the
mixture was stirred for 30 min at 0 °C. Compound (S)-4 (360 mg,
1.175 mmol, 1 equiv) in 5 mL of toluene was cooled to -35 °C. The
Red-Al/morpholine mixture was slowly added to the (S)-4solution.
The reaction mixture was stirred and slowly warmed to -20 °C.
After 1 h, the reaction was complete and 1.5 mL of 4 N NaOH
was added at -20 °C, and then allowed to warm to room
temperature during 1 h. The reaction mixture was extracted
twice with AcOEt. The combined organic layers were washed
with H2O and brine, dried over MgSO4, filtered, and evaporated
to dryness. The aldehyde (S)-15 was isolated as a colorless oil.
Yield: 296 mg, 91%. 1H NMR (CDCl3, 400 MHz) δ 9.83 (s, 1 H),
7.12 (s, 1 H), 7.11 (s, 1 H), 5.90-6.01 (m, 1 H), 5.08-5.16 (m,
2 H), 3.93 (s, 3 H), 3.92 (s, 3 H), 3.75-3.80 (m, 1 H), 2.55-2.58 (t,
J = 5.8 Hz, 2 H), 1.12-1.17 (m, 1 H), 0.49-0.56 (m, 2 H),
0.22-0.30 (m, 2 H). 13C NMR (CDCl3, 100 MHz) δ 191.5,
154.5, 152.8, 134.5, 131.9, 117.9, 113.3, 106.5, 84.3, 61.4, 56.6,
52.6, 39.8, 30.1, 26.0, 15.4, 4.0, 2.7. LCMS ESIþ: method A, not
ionizing. Rt: 2.55 min. UV: 230, 285 nm. Chiral HPLC: method
1, 73% ee. HRMS: [M þ Na]þ calcd for C16H20O4 299.1254,
obsd 299.1249.
Experimental Section
General Procedure for Enzymatic Resolution. To a solution of
6 rac (1 g, 8.91 mmol) in hexane (100 mL) were added vinyla-
cetate (2.47 mL, 26.745 mmol, 3 equiv) and the corresponding
enzyme (ratio of enzyme and alcohol are outlined in Tables 1
and 2). The mixture was stirred 24 h at room temperature. The
slurry was filtered off and the enzymatic residue was washed
with 20 mL of hexane. This mixture was then poured directly
onto a silica gel column and eluted with pentane 100%, pentane/
diethyl ether 4:1, pentane/diethyl ether 1:1, then diethyl ether
100% to separate the acylated product (R)-6-Ac (first eluted)
from the nonacetylated (S)-6 (second eluted). Rf (AcOEt/cHex
1:9) = 0.47 for (R)-6-Ac and 0.13 for the alcohol (S)-6. Yields
and enantiomeric purity are summarized in Tables 1 and 2 (for
further details see the Supporting Information).
3-((S)-1-Cyclopropylbut-3-enyloxy)-4,5-dimethoxybenzoic Acid
Methyl Ester, (S)-4. Under N2, the benzoic methyl ester 5 (1 g,
4.71 mmol, 1 equiv) was dissolved in THF (13 mL). The homo-
allylic alcohol (R)-6 (0.528 g, 4.71 mmol, 1 equiv), PPh3 (1.234 g,
4.71 mmol, 1 equiv), and NEt3 (0.1 mL, 0.707 mmol, 0.15 equiv)
were added. The mixture was cooled to 0 °C, then DIAD (0.931 mL,
4.71 mmol, 1 equiv) in 2 mL of THF was added dropwise. The
reaction mixture was allowed to stir at room temperature for 2 h,
the reaction mixture was checked by LCMS and TLC, and the
same amounts of homoallylic alcohol, PPh3, and DIAD were
added to complete the reaction. TLC (AcOEt/cHex 1:9, Rf 0.21,
stained with vanillin). The reaction mixture was evaporated to
dryness, and then purified by FC (AcOEt/cHex 1:9) to give (S)-4
as a colorless oil. Yield: 1.05 g, 73%. 1H NMR (CDCl3, 400 MHz)
δ 7.25 (d, J = 1.6 Hz, 1 H), 7.22 (d, J = 1.6 Hz,1 H), 5.86-5.96
(m, 1H), 5.00-5.1(m, 2 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.82 (s, 3H),
3.67-3.72 (m, 1 H), 2.49-2.51 (t, J = 6.25 Hz, 2 H), 1.03-1.12
(m, 1 H), 0.40-0.50 (m, 2 H), 0.15-0.28 (m, 2 H). 13C NMR
N-[5-[3-((S)-1-Cyclopropylbut-3-enyloxy)-4,5-dimethoxybenzyl]-
4-(2,2-dimethylpropionylamino)pyrimidin-2-yl]-2,2-dimethylpropio-
namide, (S)-16. To a solution of the aldehyde (S)-15 (465 mg, 1.68
mmol, 1 equiv) in DMSO (5 mL) under N2 was added anilinopro-
pionitrile (271 mg, 1.85 mmol, 1.1 equiv). tBuOK (217 mg, 1.93
mmol, 1.15 equiv) was then added and the mixture was stirred for
1 h at room temperature. The reaction mixture was checked by
LCMS then worked up with a mixture of AcOEt and H2O. The
layers were separated and the aqueous layers were reextracted with
AcOEt. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and evaporated to dryness. The
resulting crude material was used for the next step without further
3784 J. Org. Chem. Vol. 75, No. 11, 2010

Tahtaoui et al.
JOCArticle
purification. Guanidine HCl (484 mg, 5.04 mmol, 3 equiv) was
added. The aqueous phase was extracted twice with AcOEt. The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and evaporated to dryness. Any attempt to purify
the aldehyde (S)-17 by FC decomposed the product; therefore the
crude material was used without further purification. The crude
aldehyde (S)-17 was dissolved in CH2Cl2 (2 mL), then cooled to
0 °C. TFA (0.45 mL, 5.92 mmol, 16 equiv) and TFAA (413 μL,
2.96 mmol, 8 equiv) were added at 0 °C. The reaction mixture was
stirred at room temperature for 150 min. The reaction mixture was
then poured into a saturated solution of NaHCO3 and extracted
twice with AcOEt. The combined organic layers were washed with
brine, dried over MgSO4, filtered, and evaporated to dryness. FC
with AcOEt/cHex 1:1 gave 126 mg of (R)-18 (65%) as a white
solid. 1H NMR (CDCl3, 400 MHz) δ 8.19 (s, 1 H), 8.12 (s, 1 H),
8.00 (s, 1 H), 6.38 (d, J = 10 Hz, 1 H), 6.16 (s, 1 H), 5.67 (dd, J1 =
10.2 Hz, J2= 3.4 Hz, 1 H), 4.19 (dd, J1 = 8.4 Hz, J2= 3.4 Hz, 1H),
3.87 (s, 2 H), 3.80 (s, 2 H), 3.75 (s, 3 H), 1.30 (s, 9 H), 1.21 (s, 9 H),
0.43-0.61 (m, 3 H), 0.26-0.34 (m, 2 H). 13C NMR (CDCl3,
100 MHz) δ 176.8, 176.1, 159.9, 156.9, 155.7, 153.2, 147.6, 136.6,
127.8, 123.2, 120.7, 120.4, 115.4, 105.6, 78.8, 61.0, 56.0, 49.4, 40.2,
39.9, 31.5, 27.3, 27.1, 26.9, 15.2, 2.8, 1.5. LCMS ESIþ: method A
m/z 523.3 [M þ H]þ. Rt: 2.43 min. UV: 245 (280) nm. Chiral
HPLC: method 3, 74% ee.
3
dissolved in dry EtOH (5 mL) before adding tBuOK (566 mg, 5.04
mmol, 3 equiv). The mixture was stirred for 30 min at room
temperature, then the white precipitate was filtered off and washed
with 5 mL of EtOH. The ethanolic guanidine solution was added to
the anilinopropionitrile adduct and the mixture was heated for 12 h
at 90 °C. The solvent was evaporated and the residue was dissolved
in AcOEt and H2O. The layers were separated, and the organic
layer was washed with brine, dried over MgSO4, filtered, and
evaporated to dryness to give product (S)-3 as a brown solid. The
brown solid was dissolved in pivalic anhydride (0.85 mL, 4.2 mmol,
2.5 equiv) and the mixture was heated at 150 °C for 1 h. AcOEt was
added and the mixture was washed with 10 mL of H2O/NH4OH
24% 1:1. The mixture was extracted twice with AcOEt; the
combined organic layers were washed with brine, dried over
MgSO4, filtered, and evaporated to dryness. FC (AcOEt/cHex
1:4 then 2:3 then 4:1) gave (S)-16 as a white solid in 70% yield (633
mg). 1H NMR (CDCl3, 400 MHz) δ 8.31 (br s, 1 H), 8.10 (br s,
1 H), 6.35 (s, 1 H), 6.31 (s, 1 H), 5.85-5.96 (m, 1 H), 5.03-5.11 (m,
2 H), 3.85 (s, 2 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.63-3.65 (m, 1 H),
2.47-2.50 (t, J = 6 Hz, 2 H), 1.34 (s, 9 H), 1.14 (s, 9 H), 1.05-1.13
(m, 1 H), 0.45-0.70 (m, 2 H), 0.18-0.26 (m, 2 H). 13C NMR
(CDCl3, 100 MHz) δ 176.7, 160.6, 157.6, 156.6, 154.5, 152.9, 139.6,
134.7, 133.0, 119.3, 117.6, 111.6, 106.4, 84.0, 61.2, 56.6, 40.7, 40.4,
39.9, 35.7, 30.1, 27.8, 27.6, 15.4, 3.9, 2.6. LCMS ESIþ: method A,
m/z 539.3 [M þ H]þ. Rt: 2.57 min. UV: 245, 275 nm. Chiral HPLC:
method 2, 74% ee. HRMS: [M þ Na]þ calcd for C30H42N4O5
561.3047, obsd 561.3037.
€
Acknowledgment. We thank Dr. D. Haussinger (Depart-
ment of Chemistry, University of Basel) for assistance
regarding NMR analysis.
N-[5-((R)-2-Cyclopropyl-7,8-dimethoxy-2H-chromen-5-ylmethyl)-
4-(2,2-dimethylpropionylamino)pyrimidin-2-yl]-2,2-dimethylpropio-
namide, (R)-18. To a solution of (S)-16 (200 mg, 0.37 mmol,
1 equiv) in THF (2 mL) was added NaIO4 (0.2 g, 0.93 mmol,
Supporting Information Available: Experimental details and
characterizations for 1, 4, 6, 9, 10, 11, 12, 14, 15, 16, 18, and
Mosher’s esters of (R)-6; 1H and 13C for all compounds; chiral
GC spectra for 6 rac, (R)-6, and (S)-6; and chiral HPLC for 1, 4,
14, 15, 16, and 18. This material is available free of charge via the
Internet at http://pubs.acs.org.
2.5 equiv), K2OsO4 2H2O (6.8 mg, 0.018 mmol, 0.05 equiv), and
3
0.5 mL of H2O at room temperature. The oxidation was complete
after 1 h. AcOEt, H2O, and a saturated solution of Na2S2O3 were
J. Org. Chem. Vol. 75, No. 11, 2010 3785