An efficient enantioselective synthesis of (2R)-hydroxymethyl glutamic acid and an approach to the (2R)-hydroxymethyl-substituted sphingofungins

Article abstract of DOI:10.1021/jo052408q

We have developed a short enantioselective synthesis of (2R)-hydroxymethyl glutamic acid (HMG) starting from Garner's aldehyde using an alkylidene carbene 1,5-CH insertion as a method to construct the quaternary stereocenter. A variety of conditions were examined for the oxidative cleavage of the key cyclopentene intermediate and we found that RuCl₃/NaIO₄ led directly to the desired amino bis-acid product. We were also able to show that oxidative cleavage of the cyclopentene 1,5-CH insertion product could be used to produce the amino acid-containing skeleton of the sphingofungin family of natural products.

Full text of DOI:10.1021/jo052408q

An Efficient Enantioselective Synthesis of (2R)-Hydroxymethyl
Glutamic Acid and an Approach to the
(2R)-Hydroxymethyl-Substituted Sphingofungins
Christopher J. Hayes,*,† Daniel M. Bradley,† and Nicholas M. Thomson‡
The School of Chemistry, UniVersity of Nottingham, UniVersity Park, Nottingham,
NG7 2RD, United Kingdom, and Pfizer Global Research and DeVelopment,
Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
chris.hayes@nottingham.ac.uk
ReceiVed NoVember 21, 2005
We have developed a short enantioselective synthesis of (2R)-hydroxymethyl glutamic acid (HMG) starting
from Garner’s aldehyde using an alkylidene carbene 1,5-CH insertion as a method to construct the
quaternary stereocenter. A variety of conditions were examined for the oxidative cleavage of the key
cyclopentene intermediate and we found that RuCl3/NaIO4 led directly to the desired amino bis-acid
product. We were also able to show that oxidative cleavage of the cyclopentene 1,5-CH insertion product
could be used to produce the amino acid-containing skeleton of the sphingofungin family of natural
products.
Introduction
also disclosed syntheses of enantiopure HMG 2. These publica-
tions highlight a variety of contemporary synthetic methods
available for the enantioselective construction of R-alkylserine
derivatives, and we now wish to report our own initial work in
this area.
During a research program examining the use of alkylidene
carbene 1,5-CH insertion reactions in asymmetric synthesis,7a-f
we were able to complete an enantioselective total synthesis of
The novel R,R-dialkyl-R-amino acid (2R)-hydroxymethyl
glutamic acid (HMG) 2 was first synthesized by Kozikowski
et al. as part of an ongoing program to produce more specific
glutamate receptor agonists and antagonists.1 During this study
it was found that 2 was a potent mGluR3 agonist and a weak
mGluR2 antagonist and since this initial report, Langlois,2
Ohfune,3 Park and Jew,4 Battistini and Casiraghi,5 and Ma6 have
(5) Battistini, L.; Curti, C.; Zanardi, F.; Rassu, G.; Auzzas, L.; Casiraghi,
G. J. Org. Chem. 2004, 69, 2611.
(6) Tang, G.; Tian, H.; Ma, D. Tetrahedron 2004, 60, 10547.
† University of Nottingham.
‡ Pfizer Global Research and Development.
(1) Zhang, J.; Flippen-Anderson, J. L.; Kozikowski, A. P. J. Org. Chem.
2001, 66, 7555.
(2) (a) Choudhury, P. K.; Le Nguyen, B. K.; Langlois, N. Tetrahedron
Lett. 2002, 43, 463. (b) Langlois, N.; Le Nguyen, B. K. J. Org. Chem.
2004, 69, 7558.
(3) Kawasaki, M.; Namba, K.; Tsujishima, H.; Shinada, T.; Ohfune, Y.
Tetrahedron Lett. 2003, 44, 1235.
(4) (a) Lee, J.; Lee, Y.-I.; Kang, M. J.; Lee, Y.-J.; Jeong, B.-S.; Lee,
J.-H.; Kim, M.-J.; Choi, J.-Y.; Ku, J.-M.; Park, H.-G.; Jew, S.-S. J. Org.
Chem. 2005, 70, 4158. (b) Lee, Y.-J.; Lee, J.; Kim, M.-J.; Jeong, B.-S.;
Lee, J.-H.; Kim, T.-S.; Lee, J.; Ku, J.-M.; Jew, S.-S.; Park, H.-G. Org.
Lett. 2005, 7, 3207.
(7) (a) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. J.
Org. Chem. 2002, 67, 7613. (b) Green, M. P.; Prodger, J. C.; Hayes C. J.
Tetrahedron Lett. 2002, 43, 6609. (c) Worden, S. M.; Mapitse R.; Hayes,
C. J. Tetrahedron Lett. 2002, 43, 6011. (d) Mapitse, R.; Hayes, C. J.
Tetrahedron Lett. 2002, 43, 3541. (e) Green, M. P.; Prodger, J. C.; Sherlock,
A. E.; Hayes, C. J. Org. Lett. 2001, 3, 3377. (f) Gabaitsekgosi, R.; Hayes,
C. J. Tetrahedron Lett. 1999, 40, 7713. (g) Grainger, R. S.; Owoare, R. B.
Org. Lett. 2004, 6, 2961. (h) Sasakai, A.; Aoyama, T.; Shiori, T. Tetrahedron
Lett. 2000, 41, 6859. (i) Taber, D. F.; Han, Y.; Incarvito, C. D.; Rheingold,
A. L. J. Am. Chem. Soc. 1998, 120, 13285. (j) Taber, D. F.; Meagley, R.
P.; Walter, R. J. Org. Chem. 1994, 59, 6014. (k) Ohira, S.; Ishi, S.;
Shinohara, K.; Nozaki, H. Tetrahedron Lett. 1990, 31, 1039.
10.1021/jo052408q CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/01/2006
J. Org. Chem. 2006, 71, 2661-2665
2661

Hayes et al.
SCHEME 1
procedure.7a The 1,5-CH insertion precursor 10 was prepared
from (S)-Garner’s aldehyde11 6 via the enone 8, and then
exposed to lithio-TMS-diazomethane at low temperature (-78
°C).12 Upon warming to 0 °C, the desired cyclopentene product
3 was formed in good yield and in excellent enantiomeric excess
(>97% ee)7a (Scheme 1).
FIGURE 1.
the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-diarboxy-
lic acid (ACPD) 1.7a This synthesis relied upon the exquisite
1,5-insertion selectivity of alkylidene carbenes to form an
advanced cyclopentene synthetic intermediate 3. We were then
able to convert this material into the desired target 1 using
standard functional group interconversions. The 1,5-CH insertion
reaction is obviously well suited to the synthesis of cyclopentene
and cyclopentane-containing targets, but we wished to broaden
the scope of this synthetic strategy to allow access to acyclic
target molecules. During our recent total synthesis of the natural
product (-)-TAN1251 A we were able to utilize an alkylidene
carbene 1,5-CH insertion to form a key quaternary center,8 but
we needed to perform a ring expansion reaction on a key
cyclopentene CH-insertion product to provide the cyclohexane
ring present in the natural product. This was readily accom-
plished by an oxidative cleavage-aldol condensation strategy.9
Due to the success of this synthetic approach, we wondered
whether similar oxidative cleavage reactions could be applied
to the synthesis of other acyclic target structures. In particular
we saw that the cyclopentene 3 used in our ACPD 1 synthesis
gave us the opportunity to prepare a range of R-alkylserine
derivatives. Oxidative cleavage of the olefin in 3, using
ozonolysis for example, should afford the acyclic keto-aldehyde
product 4. We felt that this material would be an ideal precursor
to HMG 2, with the synthesis being completed using a few
relatively straightforward synthetic steps. We also noted that
the keto-aldehyde 4 had a substitution and oxidation pattern
similar to that of the polar headgroup of the sphingofungins10
(e.g. sphingofungin E 5), and wondered whether we could use
this 1,5-CH insertion-oxidative cleavage approach to access
this important class of biologically active natural products.
Having secured a reliable route to 3 we were now in a position
to explore the oxidative cleavage conditions required to produce
the keto-aldehyde 4. Ozonolysis was initially explored, and the
desired keto-aldehyde 12 could be isolated in a modest 32%
yield. Unfortunately, we were not able to optimize this reaction
and we therefore turned our attention to alternative conditions.
As we had already successfully prepared the diol 11 from 3
during our synthesis of ACPD 1, we wondered whether 11 could
be cleaved with sodium periodate to produce 12. The diol 11
was therefore prepared in high yield via an Upjohn dihydroxy-
lation,13 and upon treatment with 1 equiv of NaIO4 the desired
keto-aldehyde 12 was produced in 80% yield (Scheme 2). When
the diol 11 was exposed to an excess of NaIO4 (4 equiv) we
were pleased to find that the carboxylic acid 13 was produced
in excellent yield (96%). We believe that this product is being
produced in situ via oxidative cleavage of the protected acyloin
moiety of 12, and this discovery is to our considerable advantage
as cleavage of this C-C bond is required in our proposed
synthesis of 2. As NaIO4 can be used as the co-oxidant in OsO4-
mediated dihydroxylations, we explored the possibility of
accessing the acid 13 from 3 in a one-pot procedure.14 After
some initial optimization, we were pleased to find that oxidation
of 3 with K2OsO4‚H2O (0.03 equiv) and NaIO4 (4 equiv)
provided the desired acid 13 in 63% yield (Scheme 2). To
complete a synthesis of HMG 2 from 13 all that remained was
(10) (a) Aragozzini, F.; Manachini, P. L.; Craveri, R. Tetrahedron 1972,
28, 5493. (b) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.;
Toyama, R.; Chiba, K.; Hoshino, Y.; Okumoto, T. J. Antibiot. 1994, 47,
208. (c) Miyake, Y.; Kozutsumi, Y.; Nakamura, S.; Fujita, T.; Kawasaki,
T. Biochem. Biophys. Res. Commun. 1995, 211, 396. (d) Horn, W. S.; Smith,
J. L.; Bills, G. F.; Raghoobar, S. L.; Helms, G. L.; Kurtz, M. B.; Marrinan,
J. A.; Frommer, B. R.; Thornton, R. A.; Mandala, S. M. J. Antibiot. 1992,
1692. (e) Sasaki, S.; Hasimoto, R.; Kiuchi, M.; Inoue, K.; Ikumoto, T.;
Hirose, R.; Chiba, K.; Hoshino, Y.; Okumoto, T.; Fujita, T. J. Antibiot.
1994, 47, 420. (f) Fujita, T.; Hamamichi, N.; Kiuchi, M.; Matsuzaki, T.;
Kitao, Y.; Inoue, K.; Hirose, R.; Yoneta, M.; Sasaki, S.; Chiba, K. J.
Antibiot. 1996, 49, 846.
Results and Discussion
To achieve a synthesis of 2 our first task was to prepare
multigram quantities of the key cyclopentene intermediate 3,
and this was readily achieved using our previously published
(8) Auty, J. M. A.; Churcher, I.; Hayes, C. J. Synlett 2004, 1443.
(9) (a) Taber, D. F.; Liang, J.-L.; Chen, B.; Cai, L. J. Org. Chem. 2005,
70, 8739. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768. (c)
Taber, D. F.; Neubert, T. D.; Rheingold, A. L. J. Am. Chem. Soc. 2002,
124, 12416. (d) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43,
5389. (e) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. (f)
Taber, D. F.; Meagley, R. P.; Doren, D. J. J. Org. Chem. 1996, 61, 5723.
(g) Gilbert, J. C.; Giamalva, D. H.; Baze, M. E. J. Org. Chem. 1985, 50,
2557.
(11) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361 (b)
Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis 1998, 1707.
(12) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun.
1992, 721.
(13) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973. (b) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984,
40, 2247.
(14) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
2662 J. Org. Chem., Vol. 71, No. 7, 2006

Synthesis of (2R)-Hydroxymethyl Glutamic Acid
SCHEME 2 a
SCHEME 3 a
a Reagents and conditions: (a) NH(Me)OMe‚HCl, Pyr, 100%; (b)
H2CdCH(CH2)6MgBr, 74%; (c) HO(CH2)2OH, PTSA; (d) K2OsO4.2H2O,
NMO, acetone/H2O, then NaIO4/SiO2, DCM, 87% (3 steps).
tion step was then required to obtain the correct geometry. In
our approach we planned to react a stabilized ylide (e.g. 21) in
a Wittig reaction with the aldehyde 18, which should furnish
the desired E-olefin geometry directly.
a Reagents and conditions: (a) K2OsO4, NMO, acetone/H2O (94%); (b)
NaIO4 (1 equiv), THF/H2O (80%); (c) NaIO4 (4 equiv), THF/H2O (96%);
(d) K2OsO4, NaIO4 (4 equiv), THF/H2O (63%); (e) RuCl3, NaIO4
(5.8 equiv), CCl4/MeCN/H2O (88%); (f) HCl(conc), EtOAc then Dowex
50W×8-200, 2 M NH3 (aq) (85%).
As we had already prepared the keto-aldehyde 12, our first
task was to prepare the aldehyde 18 and this was readily
accomplished by using the approach shown in Scheme 3.
Formation of the Weinreb amide 16 from heptanoyl chloride
15 proceeded without problem.17 Addition of 7-octenylmagne-
sium bromide to the crude amide, followed by acidic workup
then gave the ketone 17 in high yield.18 Protection of the ketone
with ethylene glycol under Dean-Stark conditions and oxidative
cleavage (OsO4/NaIO4 on SiO219) then gave the aldehyde 18
for use in the subsequent Wittig reaction.
oxidation of the aldehyde to a carboxylic acid and removal of
the Boc and aminal protecting groups.
Although a wide variety of conditions were potentially
available for oxidation of the aldehyde 13 to the acid 14, we
were particularly attracted to methods that were compatible with
our tandem olefin/acyloin oxidative cleavage conditions, as this
opened up the possibility of developing a one-pot procedure
for the synthesis of the diacid 14 from the cyclopenetene 3.
The RuCl3/NaIO4-mediated oxidation procedure of Sharpless15
seemed ideally suited to our needs as this reagent combination
not only provides a mild method of accessing carboxylic acids
from aldehydes, but is also capable of performing oxidative
cleavage of olefins to provide carboxylic acid products. We
reasoned that replacing OsO4 with RuO4 (generated in situ from
RuCl3) would allow us to access the desired diacid 14 from 3
in one synthetic operation, thus removing the need to perform
several individual oxidations. To our delight, we found that
exposure of the cyclopentene 3 to RuCl3 (0.06 equiv) and NaIO4
(5.8 equiv) in CCl4/MeCN/H2O afforded the desired dicarboxy-
lic acid 14 in excellent yield (88%). Deprotection of the diacid
14 with HCl (conc) in EtOAc followed by ion exchange
chromatography (Dowex 50W×8-200, 2 M NH3 aq) finally
afforded (2R)-HMG 2 as a white solid (Scheme 2).
Having successfully completed a synthesis of (2R)-HMG 2
from 3 we were keen to see if we could use the keto-aldehyde
12 to access the polar headgroup of the (2R)-hydroxymethyl-
substituted sphingofungins (e.g. 5).16 We envisaged that the C5-
ketone in 12 could become the C5-carbinol in a target molecule
such as 5 and that the C6-C7 double bond could be constructed
using a Wittig olefination. A Wittig reaction has been used
previously for this bond construction;16a however, the reaction
was performed using a non-stabilized ylide leading to the
formation of the undesired Z-alkene and a subsequent equilibra-
Our next task was to develop a suitable procedure for
oxidizing the aldehyde 12 to the corresponding carboxylic acid
without cleaving the protected acyloin moiety. We had already
shown that NaIO4 mediates cleavage of this functionality, so
we were particularly careful to avoid conditions incorporating
this, or any other glycol-cleaving oxidants. Pleasingly we found
that sodium chlorite was an excellent reagent for this oxidation
and the resulting acid was converted to its methyl ester 19 by
treatment with TMS-diazomethane (75%, 2 steps). Deprotection
of the TBS-ether 19 with buffered TBAF then gave the
corresponding alcohol 20 in good yield. Having constructed the
protected R,R-dialkyl-R-amino acid 20, we then needed to
develop a Wittig olefination procedure for its connection to the
aldehyde 18. Fortunately, elaboration of the acyloin moiety
present in 20 into the required phosphorane 21 was relatively
straightforward and was accomplished as shown in Scheme 4.
Thus, activation of the alcohol 20 as its mesylate 22 and
subsequent treatment with triphenylphosphine first provided a
phosphonium salt. Deprotonation with Et3N then afforded the
phosphorane 21, which was reacted in situ with the previously
prepared aldehyde 18 to afford the desired enone 23 as the
required E-geometric isomer. After extensive optimization of
this procedure we were able to develop a one-pot procedure,
giving 61% of 23 starting from the alcohol 20, which removes
the need to handle any of the sensitive and/or polar intermediates
involved. To achieve a total synthesis of sphingofungin E 5 we
next need to develop a protocol for introducing the required
oxygenation at C3 and C4 of the enone 23 and these studies
are currently underway in our laboratory, and progress will be
reported in due course.
(15) Calsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936.
(16) (a) Wang, B.; Yu, X.-M.; Lin, G.-Q. Synlett 2001, 904. (b)
Nakamura, T.; Shiozaki, M. Tetrahedron Lett. 2001, 42, 2701. (c) Nakamura,
T.; Shiozaki, M. Tetrahedron 2002, 58, 8779. (d) Oishi, T.; Ando, K.;
Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Org. Lett. 2002, 4, 151 (e)
Spingofungin E: Lee C. B. Ph.D. Thesis, Stanford University, 1999. And
for an analogous route to sphingofungin F see: (f) Trost, B. M.; Lee, C. B.
J. Am. Chem. Soc. 1998, 120, 6818.
(17) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(18) The synthesis of the ketone 17 followed a similar route to that used
by Trost for a homologous compound (see refs 15d and 15e).
(19) NaIO4 on silica was prepared according to the procedure given in
the following: Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62,
2622.
J. Org. Chem, Vol. 71, No. 7, 2006 2663

Hayes et al.
SCHEME 4 a
(6H, s); δC (101 MHz, CD3C6D5, 368 K) 152.2, 94.6, 80.0, 78.8,
76.1, 71.9, 71.5, 70.0, 31.8, 31.1, 29.0, 26.8, 26.5, 18.9, -4.3; m/z
(ES+) 454.2629 (M + Na; C21H41NNaO6Si requires 454.2601).
(4R)-4-[4-(tert-Butyldimethylsilyloxy)-3-oxobutyl]-4-formyl-
2,2-dimethyloxazolidine-3-carboxylic Acid tert-Butyl Ester (12).
NaIO4 (770 mg; 3.60 mmol) was added in one portion to a stirring
solution of diol 11 (1.56 g; 3.60 mmol) in THF/water (2:1, 17 mL).
The mixture was stirred for 2.5 days, adsorbed onto silica (ethyl
acetate used to azeotrope water), and filtered through a plug of
silica. Concentration in vacuo gave a slightly yellow oil (1.46 g)
that was purified by column chromatography (4:1, petrol/Et2O),
yielding aldehyde 12 (1.24 g; 80%) as a colorless oil [R]27D -8.56
(c 1.92, CHCl3) (found: C 59.15, H 8.9, N 3.0. C21H39NO6Si
requires C 58.7, H 9.2, N 3.3); νmax/cm-1 (film) 1740 (CO), 1709
(CO), 1689 (CO); δH (500 MHz; CDCl3, 1.5:1 mixture of rotamers)
9.48/9.42 (1H, s), 4.16 (2H, app s), 3.92maj/3.91min (1H, d, Jmaj
)
9.7 Hz, Jmin ) 9.5 Hz), 3.79maj/3.73min (1H, d, Jmaj ) 9.7 Hz, Jmin
) 9.5 Hz), 2.79-2.67 (1H, m), 2.65-2.55 (1H, m), 2.34-2.15
(2H, m), 1.66/1.603 (3H, s), 1.595/1.57 (3H, s), 1.48/1.41 (9H, s),
0.91 (9H, s), 0.08 (6H, s); δC (126 MHz; CDCl3, 1.5:1 mixture of
rotamers) 210.1, 197.9/197.7, 152.2/150.9, 96.4/95.4, 81.8/81.5,
71.1/70.1, 69.4/69.3, 67.7, 33.4/33.0, 28.4/28.2, 26.7, 25.9,
25.6/25.4, 24.7, 24.2, 18.4, -5.4; m/z (ES+) 452.2461 (M + Na;
C21H39NNaO6Si requires 452.2444).
(4R)-4-(2-Carboxyethyl)-4-formyl-2,2-dimethyloxazolidine-3-
carboxylic Acid tert-Butyl Ester 13 (via oxidative cleavage of
cyclopentene 3). K2OsO4‚2H2O (4.70 mg; 12.8 µmol) was added
in one portion to a stirring solution of cyclopentene 3 (173 mg;
0.44 mmol) and NaIO4 (378 mg; 1.77 mmol) in THF (1.2 mL) and
water (0.6 mL). The mixture was stirred for 6 days, quenched with
Na2SO3 (206 mg; 1.63 mmol) and water (1 mL), and stirred for a
further 30 min. The mixture was adsorbed onto silica (ethyl acetate
used to azeotrope water), filtered through a plug of silica/Celite/
sand, and concentrated in vacuo, giving a brown oil (261 mg). This
was purified by column chromatography (petrol/ethyl acetate/glacial
acetic acid 8/4/0.1), giving the air sensitive (the aldehyde readily
oxidizes to a carboxylic acid upon standing in air) acid 13
a Reagents and conditions: (a) NaClO2, H2CdCMe2, NaH2PO4, tBuOH;
(b) TMSCHN2, MeOH, PhH (75%, 2 steps); (c) TBAF, THF/H2O/HOAc
(77%); (d) MsCl, Et3N, CH2Cl2; (e) PPh3, Et3N, CH2Cl2; (f) 18, CH2Cl2
(61%, 3 steps).
In conclusion, we have shown that an alkylidene carbene 1,5-
CH insertion reaction can be used to effect an efficient total
synthesis of the potent mGluR3 agonist (2R)-hydroxymethyl
glutamic acid (HMG) 2. The synthesis is accomplished in an
overall yield of 36%, over 5 steps from (S)-Garner’s aldehyde,
and represents one of the most efficient enantioselective
syntheses of this important compound to date. We have also
shown that oxidative cleavage of the spirocycle 3 can also
provide hydroxymethyl-substituted amino acid fragments (e.g.
20) for future use in the synthesis of a variety of sphingofungin
natural products (e.g 5) and their analogues.
(83.4 mg; 63%) as a colorless oil [R]28 -6.6 (c 3.47, CHCl3);
D
ν
max/cm-1 3458br (OH), 3203 br (OH), 1739 (CO), 1712 (CO) 1683
(CO); δH (500 MHz, CDCl3, 1.6:1 mixture of rotamers) 9.45/9.38
(1H, s), 3.92maj/3.91min (1H, d, Jmaj ) 9.7 Hz, Jmin ) 9.5 Hz),
3.90maj/3.75min (1H, d, Jmaj ) 9.7 Hz, Jmin ) 9.5 Hz), 2.57-2.13
(4H, m), 1.65/1.60 (3H, s), 1.59/1.57 (3H, s), 1.47/1.40 (9H, s); δC
(126 MHz, CDCl3, 1.6:1 mixture of rotamers) 197.5/197.3,
197.4/179.3, 152.2/150.8, 96.6/95.5, 82.2/81.9, 70.9/70.5, 67.5/67.4,
29.1/28.9, 28.3/28.2, 26.7, 26.4/26.3, 25.6, 25.2, 24.0; m/z (ES+)
324.1387 (M + Na; C14H23NNaO6 requires 324.1423).
Experimental Section
(4R)-4-(2-Carboxyethyl)-4-formyl-2,2-dimethyloxazolidine-3-
carboxylic Acid tert-Butyl Ester 13 (via oxidative cleavage of
diol 11). NaIO4 (291 mg; 1.36 mmol) was added in one portion to
a stirring solution of diol 11 (146 mg; 0.34 mmol) in THF/water
(2:1; 2 mL). The resulting mixture was stirred at room temperature
for a further 17.5 h. The reaction was quenched with Na2SO3 (180
mg; 1.42 mmol) in water (2 mL). The organic solvent was re-
moved in vacuo, and the remaining aquoeus was extracted with
i-PrOH/CHCl3 (1:1; 20 mL). The organic phase was dried (MgSO4)
and concentrated in vacuo, giving acid 13 as a yellow oil (98.1
mg; 96%), which was used without further purification . The data
recorded were identical with those reported above.
(4R)-4-(2-Carboxyethyl)-2,2-dimethyloxazolidine-3,4-dicar-
boxylic Acid 3-tert-Butyl Ester (14). RuCl3 (anhydrous; 5.0 mg;
24.1 µmol) was added in one portion to a stirring solution of
cyclopentene 3 (156 mg; 0.39 mmol) and NaIO4 (484 mg; 2.26
mmol) in CCl4 (0.75 mL), CH3CN (0.75 mL), and H2O (1.13 mL).
The mixture was stirred at room temperature for 12 days. Diethyl
ether (2 mL) was added and the mixture was stirred for a further
30 min (the RuO4 oxidizes the diethyl ether). The mixture was
adsorbed onto silica (ethyl acetate used to azeotrope water), filtered
through a silica/Celite/sand plug, and concentrated in vacuo, giving
(5S,6R,7R)-7-(tert-Butyldimethylsilyloxymethyl)-6,7-dihydroxy-
2,2-dimethyl-3-oxa-1-azaspiro[4.4]nonane-1-carboxylic Acid tert-
Butyl Ester (11). N-Methylmorpholine N-oxide (1.34 g; 9.91 mmol)
was added in one portion to a stirring solution of cyclopentene 3
(1.31 g; 3.30 mmol) in acetone/water (10:1; 143 mL). K2OsO4‚
2H2O (121 mg; 0.33 mmol) was then added in one portion, and
the resulting mixture was stirred at room temperature for a further
4.5 days. The reaction was quenched with Na2SO3 (1.26 g; 10.0
mmol) and concentrated in vacuo (water removed by azeotrope with
ethyl acetate) onto silica. The free flowing powder was slurried in
ethyl acetate and filtered through Celite, and the eluent was
concentrated in vacuo, giving a dark yellow oil (1.47 g). This was
purified by column chromatography (3:1 petrol/ethyl acetate), giving
diol 11 (1.34 g; 94%) as a colorless oil [R]25D 41 (c 3.27, CHCl3),
97% ee (Chiralpak AD, 8:92 IPA/Hexane, 1 mL/min) (found: C
58.6, H 9.4, N 3.3; C21H41NO6Si requires C 58.4, H 9.6, N 3.2);
ν
max/cm-1 (film) 3454 br (OH), 1694 (CO); δH (400 MHz,
CD3C6D5, 368 K) 4.80 (1H, br s), 4.51 (1H, d, J ) 9.2 Hz), 3.72
(1H, d, J ) 9.2 Hz), 3.59 (1H, d, J ) 9.8 Hz), 3.55 (1H, d, J ) 9.8
Hz), 2.49 (1H, s), 2.43-2.33 (1H, m), 2.22 (1H, br d, J ) 5.5 Hz),
2.06-1.96 (1H, m), 1.83-1.73 (1H, m), 1.67 (3H, s), 1.67-1.56
(1H, m(obscured)), 1.61 (3H, s), 1.47 (9H, s), 0.95 (9H, s), 0.07
2664 J. Org. Chem., Vol. 71, No. 7, 2006

Synthesis of (2R)-Hydroxymethyl Glutamic Acid
diacid 14 as a dark green oil (109 mg; 88% crude). The crude diacid
was judged pure enough by 1H NMR spectroscopy to be used
without purification in further transformations. An aliquot (61 mg)
of the crude product was purified by column chromatography
(column acidified by washing with petrolr (20 mL) containing
glacial acetic acid (10 drops); eluent 1:1 petrol/ethyl acetate), giving
57.7, H 9.0, N 2.9; C22H41NO7Si requires C 57.5, H 9.0, N 3.1);
max/cm-1 (film) 1746 (CO), 1705 (CO); δH (500 MHz; CDCl3,
ν
1.8:1 mixture of rotamers) 4.15/4.13 (2H, s), 4.02 (1H, d, J ) 9.1
Hz), 3.84/3.81 (1H, d, J ) 9.1 Hz), 3.71/3.70 (3H, s), 2.74-2.46
(2H, m), 2.42-2.11 (2H, m), 1.60/1.56 (3H, s), 1.58/1.54 (3H, s),
1.43/1.36 (9H, s), 0.88 (9H, s), 0.05/0.04 (6H, s); δH (400 MHz,
C6D6, 340 K) 3.99 (2H, d, J ) 1.4 Hz), 3.91 (1H, d, J ) 9.1 Hz),
3.68 (1H, d, J ) 9.1 Hz), 3.36 (3H, s), 2.74-2.36 (4H, m), 1.74
(6H, br s), 1.38 (9H, s), 0.93 (9H, s), 0.01 (6H, s); δC (126 MHz;
CDCl3, 1.8:1 mixture of rotamers) 210.3, 172.9/172.4, 151.8/151.2,
96.7/95.8, 80.81/80.76, 71.9/71.4, 69.4/69.3, 68.3/67.7, 52.6, 33.7/
33.3, 28.4/28.3, 27.3/26.6, 26.8, 25.9, 24.4, 18.4, -5.4; m/z (ES+)
482.2518 (M + Na; C22H41NNaO7Si requires 482.2550).
a colorless oil (44 mg; 56%). [R]25 4.4 (c 1.64, CHCl3); νmax
/
D
cm-1 3473 br (OH), 3176 br (OH), 1712 br (CO); δH (500 MHz;
CDCl3; 1.2:1 mixture of rotamers) 8.38 (2H, br s), 4.25/4.16 (1H,
d, J ) 9.2 Hz), 3.96/3.91 (1H, d, J ) 9.2 Hz), 2.56-2.17 (4H, m),
1.63/1.58 (3H, s), 1.61/1.57 (3H, s), 1.48/1.41 (9H, s); δC (126
MHz; CDCl3, 1.2:1 mixture of rotamers) 179.3/179.1/178.5/176.4,
152.8/151.1, 97.1/96.2, 82.1/81.6, 72.0/71.3, 68.2/67.4, 29.3/29.2,
29.8/28.1, 28.5/28.4, 26.5/25.9, 24.6/22.9; m/z (ES+) 340.1346
(C14H23NNaO7 requires 340.1372).
(4R)-4-(4-Hydroxy-3-oxobutyl)-2,2-dimethyloxazolidine-3,4-
dicarboxylic Acid 3-tert-Butyl Ester 4-Methyl Ester (20). TBAF
(1 M in THF; 260 µL; 0.26 mmol) was added in one portion to a
stirring solution of silyl ether 19 (101 mg; 0.22 mmol) in THF/
water/acetic acid (10:1:1 v/v; 2.5 mL), and the mixture was stirred
for 20 h. The reaction was concentrated in vacuo (water removed
by azeotrope with ethyl acetate) and purified by column chroma-
tography (1:1 petrol/diethyl ether to 1:1 petrol/ethyl acetate) giving
(2R)-2-Hydroxymethylglutamic Acid (HMG) 2. Concentrated
HCl in ethyl acetate (3 M, 2.5 mL) was added to the crude diacid
14 (36.0 mg) and the mixture was stirred for 19 h. The reaction
was was concentrated in vacuo and purified twice by ion exchange
column chromatography (Dowex 50W×8-200; 2 M NH3 aq) giving
HMG 2 (21.8 mg; 85% (2 steps)) as a white solid: mp 217 °C
the acyloin 20 (58.0 mg; 77%) as a colorless oil [R]31 -0.83 (c
dec; [R]28 -6.9 (c 2.86, H2O); δH (500 MHz; D2O) 7.22 (2H, br
D
D
1.93, CHCl3) (found: C 55.5, H 8.0, N 3.8; C16H27NO7 requires C
55.6, H,7.9, N 4.1); νmax/cm-1 (film) 3482 br (OH), 1744 (CO),
1705 (CO); δH (500 MHz; C6D6, 1.7:1 mixture of rotamers)
3.89-3.74 (3H, m), 3.50 (1H, d, J ) 9.2 Hz), 3.36/3.29 (3H, s),
2.58-2.36 (2H, m), 2.30-2.04 (2H, m), 1.73/1.60 (3H, s), 1.68/
1.56 (3H, s), 1.33/1.31 (9H, s); δC (126 MHz; C6D6, 1.7:1 mix-
ture of rotamers) 209.6/209.5, 173.1/172.5, 152.8/151.9, 97.4/96.4,
81.2/81.1, 72.4, 69.1/68.4, 68.6/68.4, 52.7/52.6, 34.3/33.8, 28.9,
28.7/28.6, 27.7/26.8, 24.8/23.5; m/z (ES+) 368.1694 (M + Na;
C16H27NNaO7 requires 368.1685).
s), 3.98 (1H, d, J ) 12.0 Hz), 3.79 (1H, d, J ) 12.0 Hz), 2.45-
2.32 (2H, m), 2.05 (2H, app t, J ) 7.7 Hz); δC (126 MHz; D2O)
180.3, 174.4, 66.2, 64.9, 31.5, 28.7; m/z (ES-) 176.0547 (M - H;
C6H10NO5 requires 176.0559). The HCl salt of HMG 2 was also
prepared for comparison to literature data1 (21.8 mg; 186 µmol),
thus HMG 2 was dissolved in 2 N HCl (10 mL) and stirred for 5
min. The solvent was removed in vacuo giving HMG‚HCl (30.6
mg) as an off-white solid: mp 266 °C dec; δH (400 MHz; D2O)
4.10 (1H, d, J ) 12.2 Hz), 3.85 (1H, d, J ) 12.2 Hz), 2.72-2.50
(2H, m), 2.30-2.16 (2H, m); δC (126 MHz; D2O) 176.1, 171.9,
64.4, 63.5, 28.1, 26.8; m/z (ES-) 176 (M - 2H).
(4R)-4-[11-(2-Hexyl[1,3]dioxolan-2-yl)-3-oxoundec-4-enyl]-2,2-
dimethyloxazolidine-3,4-dicarboxylic Acid 3-tert-Butyl Ester
4-Methyl Ester (23). Methanesulfonyl chloride (15.0 µL; 0.20
mmol) was added dropwise over 10 s to a room temperature stirring
solution of alcohol 20 (44.4 mg; 0.13 mmol) and triethylamine (55
µL; 0.39 mmol) in dry DCM (1.3 mL). After the solution was stirred
for 60 min, triphenylphosphine (54.0 mg; 0.21 mmol) followed by
n-Bu4NI (7.00 mg; 19.0 µmol) were added each in one portion to
the stirring solution. The mixture was stirred for 25 h, aldehyde 18
(70.0 mg; 0.26 mmol) in DCM (dry; 1 mL) was added in one
portion, and the reaction was stirred for a further 6 days. The
solution was loaded directly onto a silica gel column, and puri-
fied by column chromatography (3:1 petrol/diethyl ether to 2:1
petrol/diethyl ether), giving enone 23 (45.4 mg; 61%) as a colorless
(4R)-4-[4-(tert-Butyldimethylsilyloxy)-3-oxobutyl]-2,2-di-
methyloxazolidine-3,4-dicarboxylic Acid 3-tert-Butyl Ester 4-
Methyl Ester (19). A solution of sodium chlorite (80%; 7.56 g;
67.5 mmol) and sodium hydrogen orthophosphate (8.04 g; 51.5
mmol) in water (23.8 mL) was added dropwise over 1 min to a
cool (0 °C) stirring solution of the aldehyde 12 (1.21 g; 2.82 mmol)
in 2-methyl-2-butene (12.0 mL; 0.11 mol) and tert-butyl alcohol
(26.0 mL). The resulting solution was stirred at room temperature
for 16 h. The organic solvent was removed in vacuo, and the
remaining mixture was partitioned between water (50 mL) and ethyl
acetate (125 mL). The separated aqueous phase was extracted with
ethyl acetate (2 × 125 mL) and the combined organic phase dried
(MgSO4). Concentration in vacuo gave the acid as a colorless oil
(1.32 g), which was used without further purification. An aliquot
(46.8 mg) was purified by column chromatography (1:1 petrol/
acetic acid (0.1 M in ethyl acetate)), giving pure acid (38.3 mg;
oil: [R]27 -5.85 (c 0.82, CHCl3) (found: C 66.1, H 9.5, N 2.4;
D
C32H55NO8 requires C 66.1, H 9.5, N 2.4); νmax/cm-1 1746 (CO),
1705 (CO), 1699 (CO), 1674, 1632; δH (500 MHz, C6D6, 343K)
6.78 (1H, dt, J ) 15.8, 6.9 Hz), 6.06 (1H, dt, J ) 15.8, 1.4 Hz),
3.92 (1H, d, J ) 9.0 Hz), 3.70 (1H, d, J ) 9.0 Hz), 3.64 (4H,
app s), 3.38 (3H, s), 2.76-2.40 (4H, m), 1.92-1.87 (2H, m),
1.83-1.57 (10H, m), 1.55-1.41 (4H, m), 1.38 (9H, s), 1.35-1.15
(12H, m), 0.88 (3H, t, J ) 6.9 Hz); δC (126 MHz; C6D6; 343 K)
198.3, 173.4, 152.2, 146.8, 131.4, 112.7, 97.6, 80.9, 72.8, 69.1,
65.6, 52.4, 38.42, 38.35, 36.3, 33.1, 32.8, 30.69, 30.67, 30.1, 29.6,
29.1, 29.0, 26.9, 24.9, 24.8, 23.5, 14.7; m/z (ES+) 604.3806 (M +
Na; C32H55NNaO8 requires 604.3825).
93%) as a colorless oil: [R]25 14.8 (c 0.76, CHCl3) (found: C
D
56.3, H 8.8, N 3.0.; C21H39NO7Si requires C 56.6, H 8.8, N 3.1);
ν
max/cm-1 (film) 3202 br (OH), 1738 (CO), 1707 (CO), 1682 (CO);
δH (500 MHz; CDCl3, 1.2:1 mixture of rotamers) 4.41 (1H, d, J )
9.4 Hz), 4.20-4.10 (3H, m), 3.92min/3.81maj (1H, d, Jmin ) 9.0 Hz,
Jmaj ) 9.2 Hz), 2.80-2.16 (4H, m), 1.64/1.62 (3H, s), 1.564/1.558
(3H, s), 1.50/1.41 (9H, s), 0.92 (9H, s), 0.08 (6H, s); δC (126
MHz; CDCl3, 1.2:1 mixture of rotamers) 210.4/210.0, 177.9/174.4,
154.1/151.2, 97.0/96.3, 82.9/81.4, 71.9/70.9, 69.5/69.3, 69.0/67.6,
33.6/33.4, 28.5/28.4, 27.1/26.4, 25.9, 25.5, 23.1, 18.4, -5.4; m/z
(ES+) 468.2402 (M + Na; C21H39NNaO7Si requires 468.2394).
TMS-CHN2 (2 M solution in hexanes, 2.30 mL; 4.6 mmol) was
added dropwise over 5 min to a stirring solution of the previously
prepared acid (1.04 g; 2.33 mmol) in anhydrous methanol (4.65
mL) and benzene (16.0 mL). After stirring for 23.5 h the reaction
was quenched with NH4Cl (10 mL of a saturated methanolic
solution), filtered through Celite, and concentrated in vacuo giving
a yellow oil (1.03 g). This was purified by column chromatography
(4:1 petrol/diethyl ether) giving methyl ester 19 (812 mg; 75% (2
steps)) as a colorless oil: [R]26D -4.08 (c 1.25, CHCl3) (found: C
Acknowledgment. We thank the EPSRC and Pfizer Central
Research for provision of a studentship (D.M.B.), and also
AstraZeneca and the School of Chemistry, University of
Nottingham, for additional financial support.
Supporting Information Available: Synthesis and character-
ization of 17 and 18, and copies of the 1H and 13C NMR spectra of
2, 13, and 14. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO052408Q
J. Org. Chem, Vol. 71, No. 7, 2006 2665