A concise route to β-cyclopropyl amino acids utilizing 1,2-dioxines and stabilized phosphonate nucleophiles

Article abstract of DOI:10.1021/jo7024256

(Chemical Equation Presented) 1,2-Dioxines react with glycine-derived phosphonate nucleophiles via a multistep cascade reaction to give β-cyclopropyl amino acid derivatives in good yield with excellent control of the cyclopropane stereocentres. The cyclopropyl ketones were oxidized to the corresponding carboxylic esters using Baeyer-Villiger conditions. Standard deprotection protocols produced a series of known β-cyclopropyl amino acids that are selective and potent agonists or antagonists of the metabotropic glutamate receptors in excellent yields.

Full text of DOI:10.1021/jo7024256

A Concise Route to â-Cyclopropyl Amino Acids Utilizing
1,2-Dioxines and Stabilized Phosphonate Nucleophiles
Thomas D. Avery,† Ben W. Greatrex,† Daniel Sejer Pedersen,† Dennis K. Taylor,*,† and
Edward R. T. Tiekink‡
Department of Chemistry, The UniVersity of Adelaide, South Australia 5005, Australia, and Department of
Chemistry, The UniVersity of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249-0698
dennis.taylor@adelaide.edu.au
ReceiVed NoVember 25, 2007
1,2-Dioxines react with glycine-derived phosphonate nucleophiles via a multistep cascade reaction to
give â-cyclopropyl amino acid derivatives in good yield with excellent control of the cyclopropane
stereocentres. The cyclopropyl ketones were oxidized to the corresponding carboxylic esters using Baeyer-
Villiger conditions. Standard deprotection protocols produced a series of known â-cyclopropyl amino
acids that are selective and potent agonists or antagonists of the metabotropic glutamate receptors in
excellent yields.
Introduction
The cyclopropyl ring is a commonly employed structural
motif within drugs and diagnostic chemical tools due to its
rigidity and predictable geometry of pendant functional groups.1
It has been demonstrated that certain cyclopropyl analogues of
glutamate selectively bind metabotropic glutamate receptors
(mGluR) and can protect against the excitotoxic effects of
L-glutamate.1 Clinically applied, this class of drugs (Figure 1)
has the potential to treat neurological disorders such as ischemic
stroke,1 epliepsy,2 and Parkinson’s disease.3 Substitution at the
3-position of the cyclopropyl ring can modulate the mode of
action and affords ligands with significantly higher receptor
affinity and specificity.4-17 Despite recent advances,18,19 current
† The University of Adelaide.
FIGURE 1. Examples of selective agonists and antagonists of the
metabotropic glutamate receptors.
‡ The University of Texas at San Antonio.
(1) Brackmann, F.; de Meijere, A. Chem. ReV. 2007, 107, 4538-4583.
(2) Alexander, G. M.; Godwin, G. W. Epilep. Res. 2006, 71, 1-22.
(3) Marino, M. J.; Conn, P. J. Curr. Opin. Pharmacol. 2006, 6, 98-
102.
(4) Oba, M.; Nishiyama, N.; Nishiyama, K. Tetrahedron 2005, 61, 8456-
8464.
methodology is not sufficiently versatile to allow for the rapid
synthesis of a large and diverse collection of this class of
compounds. Consequently, identification of new more subtype
selective and higher affinity analogues is advancing slowly.
10.1021/jo7024256 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/07/2008
J. Org. Chem. 2008, 73, 2633-2640
2633

Avery et al.
Cascade ring-closing reactions involving phosphine oxides,20-23
phosphonates,24-26 and phosphonium salts27 have been employed
by others for the construction of cyclopropanes generally with
high stereospecificity and selectivity. We have recently reported
that 1,2-dioxines (8, Scheme 1) react with stabilized phosphorus
ylides28-32 or phosphonate nucleophiles (10)33 to afford di- and
trisubstituted cyclopropyl ketones (13). Scheme 1 outlines the
manifold common to phosphonates and shows the major
cyclopropyl product 13. In order for the cyclopropanation to
occur, the 1,2-dioxine 8 must first undergo base-induced
rearrangement to the cis-γ-hydroxyenone 9. Aryl substitution
(8, R ) Ar) allows catalytic amounts of mild bases such as
phosphorus ylides30 or lithiated phosphonates33 to be used for
the isomerization, but Co(II) catalysis28,30,31 must be used for
alkyl substituted 1,2-dioxines. Conjugate addition of the phos-
phonate nucleophile 10 to the intermediate cis-γ-hydroxy enone
gives oxaphospholane intermediate 11 which cyclizes intramo-
lecularly to furnish cyclopropane 13 via enolate 12.34 However,
if the cis-γ-hydroxy enone does not react with the phosphonate
nucleophile under the reaction conditions a number of side-
reactions are possible to give furan 14, dicarbonyl 15 or trans-
γ-hydroxy enone 16. In the presence of hydroxide or alkoxide,
both the cis-enone 9 and trans-enone 16 rapidly dimerize to
produce tetrahydrofurans 17.35 It is important to note that
phosphonate nucleophiles will not add to trans-γ-hydroxy
enones, presumably due to unfavorable steric interactions.36
We envisaged that our methodology would be amenable to
the synthesis of â-cyclopropyl amino acid derivatives by
inclusion of an amino substituent on the phosphonate nucleo-
phile (10, R2 ) NHR, Scheme 1). Protected phosphonoglyci-
nates (18, Figure 2) are commonly used for the synthesis of
dehydroamino acids37-41 and are commercially available. This
approach would generate all of the required stereogenic centers
in a single step and, coupled with subsequent Baeyer-Villiger
oxidation of the ketone, would provide the desired protected
cyclopropyl amino acids (20) in two steps (Figure 2). Standard
deprotection chemistry could then be applied to yield the
â-cyclopropyl amino acids (21). We have previously reported
one example of a 1,2-dioxine reacting with an R-substituted
phosphonate (10, R2 ) Me) to give a trisubstituted cyclopropane
with four contiguous stereogenic centers in a low yield (30%)
with no selectivity in the formation of the R-stereocenter.33 We
now wish to report the reaction of protected phosphonoglyci-
nates (18) with a series of 3,6-disubstituted 1,2-dioxines (8)
(5) Collado, I.; Pedregal, C.; Bueno, A. B.; Marcos, A.; Gonzalez, R.;
Blanco-Urgoiti, J.; Perez-Castells, J.; Schoepp, D. D.; Wright, R. A.;
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I.; Tizzano, J. P. J. Med. Chem. 2004, 47, 456-466.
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Cabrejas, L. M.; Pedregal, C.; Blanco-Urgoiti, J.; Perez-Castells, J.;
Fernandez, M. A.; Andis, S. L.; Johnson, B. G.; Wright, R. A.; Schoepp,
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285-287.
(34) A reviewer raised the point that if the cis-γ-hydroxy enones exist
as the alkoxides under the basic reaction conditions then attack by the
phosphonate nucleophile may occur from the opposite face to that described
in Scheme 1, giving rise to intermediate A. Collapse of this intermediate
via a SNi (frontside) displacement would then give rise to the cyclopropane
diastereoisomer B in the opposite enantiomeric series.
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The following scheme outlines the synthesis of cyclopropane D from trans-
γ-hydroxy enone C (reaction of which proceeds via the cis γ-hydroxy-
enone)36 of known absolute stereochemistry. The absolute stereochemistry
of cyclopropane D was established by single-crystal X-ray crystallography
and supports the mechanism for cyclopropanation shown in Scheme 1 and
rules out the alternative depicted above.52
(23) Wallace, P.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1988, 2971-
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K.; Tiekink, E. R. T. J. Org. Chem. 2001, 66, 7955-7966.
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Chem. Soc., Perkin Trans. 1 2000, 1319-1321.
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1323-1325.
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65, 5531-5546.
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D. K. Chem. Commun. 2002, 28-29.
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2006, 4 (2), 323-330.
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2634 J. Org. Chem., Vol. 73, No. 7, 2008

Concise Route to â-Cyclopropyl Amino Acids
SCHEME 1. Cyclopropanation Cascade Reaction and Alternative Reaction Outcomes
and the conversion of the products into glutamate analogues
(21) that are potent and selective inhibitors of the metabotropic
glutamate receptors.
however, at this temperature the phosphonate nucleophile did
not add to the enone and undesired side reactions predominated
if the reaction was left at -78 °C. Nucleophilic addition of
the phosphonate initialized at approximately -40 °C, how-
ever, the reaction gave higher yields at temperatures g-20 °C.
To verify these observations and further optimize the reaction
we screened a series of bases under three different reaction
conditions (Table 1).
As anticipated, LDA was superior to alkyllithium bases.
Maintaining the temperature at -20 °C resulted in moderate
yields of the desired cyclopropanes as ∼1:1 mixture of
diastereoisomers. The use of LDA as its mono-THF complex
in hexane or cyclohexane (entries 7-10) gave better yields of
cyclopropane than LDA in THF (entries 4-6). Moreover, yields
were significantly improved if the 1,2-dioxine was added to the
deprotonated phosphonate and was further improved if the 1,2-
Results and Discussion
We decided to investigate the cyclopropanation using 1,2-
dioxine 8a (Table 1) and commercially available Cbz- (22) and
Boc-protected (23) phosphonoglycines as well as an acetyl
protected phosphonate (24), prepared as previously de-
scribed.38,39 Initially, the reaction was attempted using methyl-
lithium in ether as reported by Kimber et al. for an R-methyl-
substituted phosphonate.33 However, under the reaction conditions,
<10% of the target compound was obtained (entry 1, Table 1)
and tetrahydrofurans (17, Scheme 1) predominated. We believed
that the poor result was due to insufficient basicity of the
lithiated phosphonates failing to generate the required cis-γ-
hydroxy enones 9 in a timely manner. A slightly better outcome
was achieved when n-butyllithium in hexane was used (entry
2), but again, we suspected that the low yield was due to
insufficient basicity of the lithiated phosphonate. From previous
work, we knew that the diisopropylamine byproduct from
lithiation of the phosphonate with LDA catalyzes ring-opening
to cis-γ-hydroxy enone,30 allowing the cyclopropanation cascade
reaction to proceed. Rearrangement of 1,2-dioxine to cis-γ-
hydroxy enone was indeed observed at -78 °C using LDA;
TABLE 1. Development of Cyclopropanation Cascade Reaction
entry
phosphonate
basemethod
yieldd (%)
1
2
22
22
22
22
22
22
22
22
22
22
22
22
22
22
23
23
24
24
MeLi in diethyl ethera-c
nBuLi in hexanea
<10e
15
23
38
39
20
31
53
48
51
20
17
0
3
nBuLi in hexaneb,c
LDA in THFa
4
5
LDA in THFb
6
LDA in THFc
7
LDA‚THF in cyclohexanea
LDA‚THF in cyclohexaneb
LDA‚THF in cyclohexanec
LDA‚THF in hexaneb
LiHMDS in THFa
8
9
10f
11
12
13
14
15
16
17
18
NaHMDS in THFa
a
DBU in CH2Cl2
LiTMP in THFa, c
LDA in THFb
0
0
LDA‚THF in cyclohexaneb
LDA in THFb
50
0
LDA‚THF in hexaneb
0
a 0 °C for 0.5 h, warm slowly to rt overnight. b -20 °C for 0.5 h, warm
slowly to rt overnight. c -20 °C for 5 h, warm slowly to rt overnight.
d Combined isolated yield for both diastereoisomers, obtained as ∼1:1
mixture, determined by 1H NMR of the crude reaction mixture. e Determined
by H NMR. f Reaction run at both 0.1 and 0.4 M to give the same yield.
1
FIGURE 2. Synthetic strategy toward â-cyclopropyl amino acids.
J. Org. Chem, Vol. 73, No. 7, 2008 2635

Avery et al.
SCHEME 2. Stereochemical Determination of Related
TABLE 2. Synthesis of Cyclopropanes from Phosphonates and
1,2-Dioxines
Cyclopropanes 25e and 26e
entry 1,2-dioxine phosphonate conditions products yieldc (%)
1
2
3
4
5
6
8b
8c
8d
8e
8f
22
22
22
22
23
23
a
a
a
b
a
b
25b, 26b
25c, 26c
25d, 26d
25e, 26e
27f, 28f
27f, 28f
54
47
50
67
47
66
8f
a -20 °C for 0.5 h, warm slowly to rt overnight. b -20 °C for 5 h, warm
slowly to rt overnight. c Combined isolated yield for both diastereoisomers,
obtained as a ∼1:1 mixture, determined by 1H NMR of the crude reaction
mixture.
dioxine was added neat rather than as a THF solution. No
concentration dependence was observed when the reaction was
run at 0.1 M (entry 10) and 0.4 M (entry 10). We also
investigated whether we could improve the reaction using amine
bases or by replacing the lithium counterion with sodium or
potassium. To this end, we chose to screen a wide range of
bases commonly employed in the synthesis dehydroamino acids
from phosphonoglycines [DBU,38,41-43 (i-Pr)2NEt,44 tetramethyl
guanidine,45 t-BuOK,38,39,46 NaH,38,39,47,48 KHMDS,37 and
NaOMe38] as well as LiOH, K2CO3, DABCO, and LiTMP under
a variety of conditions. However, in every case, these failed to
give any cyclopropane product. The major products in most
cases were THFs 17 (Scheme 1) in a diastereomeric ratio similar
to that previously reported.35 In addition, furan 14, diketone 15,
and trans-γ-hydroxy enone 16 were also observed depending
on conditions. LiHMDS (entry 11) and NaHMDS (entry 12)
did produce cyclopropane product in low yields and were not
pursued further as they were inferior to LDA. Exchanging the
Cbz protection group for a Boc group gave a similar result when
LDA mono-THF complex in cyclohexane was used (entry 16)
but despite repeated attempts completely failed when LDA in
THF (entry 15) was employed. The acetyl protected phosphonate
24 (entries 13 and 14) proved insoluble under the reaction
conditions and thus no product was obtained.
contaminants formed during the deprotonation are responsible
for the low-yielding reactions and the THF byproducts. More-
over, the lithiated phosphonates generated using alkyllithium
reagents (entries 1-3, Table 1) are not sufficiently basic to
catalyze the formation of the required cis-γ-hydroxy enone as
attested to by the presence of a significant amount of 1,2-dioxine
starting material in these reactions. Hence, the diisopropylamine
generated when using LDA proved essential for the cascade
reaction to initiate. To evaluate the scope of the cyclopropa-
nation, a series of 1,2-dioxines 8a-f were allowed to react with
N-Cbz- and N-Boc-protected phosphonoglycines (22 and 23)
under the optimal conditions (Table 2).
All cyclopropanes were obtained in moderate to good yield
with conserved stereochemistry about the cyclopropyl core. The
stereogenic center adjacent to the cyclopropane ring was formed
with little to no selectivity; however, the diastereomers were
separable by column chromatography. It is interesting to note
that extended reaction time at -20 °C can be beneficial with
certain 1,2-dioxines improving yields significantly (entry 5 vs
6, Table 2).
From the data in Table 1 it is clear that the base used to
lithiate the phosphonates is crucial to the reaction outcome.
Considering the sensitivity of enone 9 to hydroxide and, in
particular, alkoxide,35 it is likely that even trace amounts of these
(42) Guevel, A.-C.; Hart, D. J. J. Org. Chem. 1996, 61, 473-479.
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The stereochemistry of the cyclopropane ring was determined
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6242-6246.
using 1H NMR coupling constants combined with 2D ROESY
2636 J. Org. Chem., Vol. 73, No. 7, 2008

Concise Route to â-Cyclopropyl Amino Acids
SCHEME 3. Baeyer-Villiger Oxidation of 25a,c and
Subsequent Deprotection
SCHEME 4. Baeyer-Villiger Oxidation of 26a-c and
Subsequent Deprotection
NMR. Typically, protons in a trans relationship about the
cyclopropyl ring showed a coupling of 4.2-4.8 Hz, and a cis
relationship gave a coupling of around 8.4-9.6 Hz. Assignment
of the relative stereochemistry of the R-stereocenter was
considerably more challenging. The stereochemistry of cyclo-
propanes 25e and 26e were determined by 2D ROESY NMR
on the δ-lactone derivates 32 and 35 (Scheme 2). The initial
attempt at preparing δ-lactone 32 by treatment with tetrabuty-
lammonium fluoride only afforded the ring-opened material 33
in 37% yield. However, under acidic conditions, desilylation
proceeded smoothly to give alcohol 31, which subsequently
could be lactonized using trifluoroacetic acid giving only trace
amounts of ring-opened material 33. By the same method,
cyclopropane 26e was deprotected and cyclized to give lactone
35 with no observed ring-opening. The stereochemistry of the
R-stereocentre of the remaining cyclopropanes was determined
unambiguously by single-crystal X-ray crystallography of 26a,
26b, 27a, 6, 25d, 27f, and 28f.
SCHEME 5. Oxidation and Protecting Group Manipulation
of 25e and 27f
Having successfully demonstrated that our methodology could
produce a variety of densely substituted cyclopropanes, we
decided to investigate their potential as useful building blocks
for the synthesis of cyclopropane amino acids (Schemes 3 and
4). To this end, it was necessary to convert the pendant ketone
to the corresponding carboxylic acid. A Baeyer-Villiger
protocol using trifluoroacetic anhydride and hydrogen peroxide
worked well giving moderate to excellent yields of the desired
carboxylic esters 36a,c (Scheme 3) and 39a-c (Scheme 4).49
As expected there was no evidence of cyclopropane ring
migration onto oxygen due to its lower migratory aptitude
compared to phenyl. Synthesis of carboxylic esters 36c and 39c
using the triflouroacetic anhydride/hydrogen peroxide protocol
did not reach completion under a range of conditions and
significant amounts of starting material was recovered. As an
alternative we tried using m-CPBA. This did indeed produce
the desired Baeyer-Villiger products (36c and 39c) in high
yield; however, reaction times of 4-5 weeks were a consider-
able drawback making the triflouroacetic anhydride/hydrogen
peroxide protocol our preferred method.
Next, we proceeded to fully deprotect the Baeyer-Villiger
products through a simple three-step sequence involving a
transesterification to give bis-methyl esters 37a,c (Scheme 3)
and 40a-c (Scheme 4). Basic hydrolysis using aqueous lithium
hydroxide in THF produced bis-carboxylic acids 38a,c and 41a-
c. Catalytic hydrogenation of cyclopropanes 38a,c and 41a gave
the known cyclopropane amino acids 26 and 68,9 as well as 42a
that to the best of our knowledge has not been reported
previously.
Finally, we turned our attention to silyloxymethyl cyclopro-
panes 25e and 27f (Scheme 5). The Baeyer-Villiger protocol
employing triflouroacetic anhydride and hydrogen peroxide
unfortunately was not viable in these cases due to the presence
(49) Anastasia, M.; Allevi, P.; Ciuffreda, P.; Fiecchi, A.; Scala, A. J.
Org. Chem. 1985, 50, 321-325.
J. Org. Chem, Vol. 73, No. 7, 2008 2637

Avery et al.
δ -5.5, -5.2, 18.4, 25.9, 63.8, 79.8, 80.4, 125.3, 128.4, 128.5,
128.7, 129.0, 136.8; HRMS calcd for (M+ + Na) C17H26O3SiNa
329.1549, found 329.1541.
of an acid sensitive TBS substituent. Moreover, the oxidation
of 25e using m-CPBA proved too sluggish only producing
1
<10% of 44a after 1 week (by H NMR). The introduction of
(()-{[(3R,6S)-3,6-Dihydro-6-(2-methoxyphenyl)-1,2-dioxin-3-
yl]methoxy}(tert-butyl)dimethylsilane (8f): yield 4.11 g, 52%;
colorless oil; Rf 0.45 (10% EtOAc in hexanes, v/v); IR (neat) 1602,
1493, 1463, 1438, 1287, 1250 cm-1; 1H NMR (CDCl3, 600 MHz)
δ 0.078 (s, 3H), 0.083 (s, 3H), 0.90 (s, 9H), 3.76 (dd, J ) 10.8,
4.8 Hz, 1H), 3.83 (s, 3H), 3.94 (dd, J ) 10.8, 6.6 Hz, 1H), 4.60
(ddd, J ) 6.6, 4.8, 1.8 Hz, 1H), 6.05 (br s, 1H), 6.07-6.11 (m,
2H), 6.87-6.89 (m, 1H), 6.90-6.94 (m, 1H), 7.27-7.34 (m, 2H);
13C NMR (CDCl3, 150 MHz) δ -5.5, -5.3, 18.4, 25.9, 55.5, 63.8,
74.0, 79.7, 110.7, 120.4, 125.0, 125.4, 128.6, 129.1, 129.8, 157.4;
EIMS m/z 336 (M+, 4), 304 (32), 290 (55), 163 (96), 135 (54),
115 (30), 89 (100); HRMS calcd for (M + Na+, ESI) C18H28O4-
Si1Na1 359.1655, found 359.1660.
General Procedure for the Reactions of 1,2-Dioxines with
Phosphonates. Method A. (()-Trimethyl-Boc-R-phosphonogly-
cinate or (()-trimethyl-Cbz-R-phosphonoglycinate (0.75 mmol) was
dissolved in anhydrous THF (3 mL) and cooled to 0 °C. LDA‚
THF complex (1.5 M in cyclohexane, 0.71 mmol) was added. After
30 min, the appropriate 1,2-dioxine (0.71 mmol) was added, and
the reaction was allowed to slowly warm to room temperature
overnight. Half-saturated aqueous NH4Cl (5 mL) was added, and
the slurry was transferred to a separatory funnel with water (10
mL) and extracted with EtOAc (25 + 2 × 10 mL). The organic
phase was dried (Na2SO4), filtered, and concentrated in vacuo and
the residue purified by column chromatography.
Method B. (()-Trimethyl-Boc-R-phosphonoglycinate or (()-
trimethyl-Cbz-R-phosphonoglycinate (0.75 mmol) was dissolved
in anhydrous THF (3 mL) and cooled to -78 °C. LDA‚THF
complex (1.5 M in cyclohexane, 0.71 mmol) was added. After 30
min, the appropriate 1,2-dioxine (0.71 mmol) was added, and the
temperature was raised to -20 °C. After 30 min, the reaction
mixture was allowed to slowly warm to room temperature overnight
and then worked up and purified as described in Method A.
Method C. (()-Trimethyl-Boc-R-phosphonoglycinate or (()-
trimethyl-Cbz-R-phosphonoglycinate (0.75 mmol) was dissolved
in anhydrous THF (3 mL) and cooled to -78 °C. LDA‚THF
complex (1.5 M in cyclohexane, 0.71 mmol) was added. After 30
min, the appropriate 1,2-dioxine (0.71 mmol) was added, and the
temperature was raised to -20 °C. After 5 h, the reaction was
allowed to slowly warm to room temperature overnight and then
worked up and purified as described in method A.
an o-methoxy substituent on the phenyl ring (27f) did, however,
increase the rate of the Baeyer-Villiger reaction significantly,
producing 44b (Scheme 5), albeit contaminated with significant
amounts of deprotected cyclopropane 45. Cyclopropane 45 was
prone to decomposition, presumably Via lactonisation; in order
to suppress formation of 45 the Baeyer-Villiger oxidation was
buffered with Na2CO3, allowing formation of 44b in good yield
(63%), with no observed loss of the TBS protecting group.
Cyclopropane 44b is a protected form of the known mGluR
agonist 3.5
We also examined the possibility of selectively removing the
TBS group in the presence of a Boc group while avoiding
lactonization. This was easily accomplished using the conditions
previously described for the Cbz-protected cyclopropanes 25e
and 26e (Scheme 2). The free alcohol in cyclopropane 43
provides a useful handle for further chemical transformations13
and, hence, synthesis of a diverse collection of â-cyclopropane
amino acids after Baeyer-Villiger oxidation and deprotection.
Conclusion
Herein we have described our initial work on a new and
mechanistically interesting cyclopropanation cascade reaction
producing trisubstituted â-cyclopropyl amino acid precursors
with four contiguous stereogenic centers. The stereogenic centers
on the cyclopropyl core are formed with excellent selectivity
whereas the method at present does not provide any control of
the pendant stereogenic center. As a consequence, the method
produces two cyclopropane diastereoisomers as a ∼1:1 mixture.
The diastereoisomers are however separable and further trans-
formations can be conducted to obtain single diastereoisomers
of cyclopropyl glutamic acid analogues in a facile manner and
in excellent yields. Work is currently under way to provide
further mechanistic insight and to make the process diastereo-
selective and will be reported in due course.
Experimental Section
(() (S)-Methyl 2-[(1S,2S,3R)-2-Benzoyl-3-methylcyclopropyl]-
2-{[(benzyloxy)carbonyl]amino}ethanoate 25a: colorless solid;
mp 57-60 °C; Rf 0.40 (30% EtOAc in hexanes, v/v); IR (Nujol)
3304, 1747, 1694, 1655, 1550, 1250 cm-1; 1H NMR (CDCl3, 600
MHz) δ 1.41 (d, J ) 6.0 Hz, 3H), 1.87 (ddq, J ) 9.0, 6.0, 4.2 Hz,
1H), 1.95 (ddd, J ) 9.6, 9.0, 4.2 Hz, 1H), 2.75 (dd, J ) 4.2, 4.2
Hz, 1H), 3.80 (s, 3H), 4.28 (dd, J ) 9.6, 9.0 Hz, 1H), 5.07 (d, J )
12.0 Hz, 1H), 5.13 (d, J ) 12.0 Hz, 1H), 5.55 (br d, J ) 9.0 Hz,
1H), 7.27-7.29 (m, 5H), 7.42-7.45 (m, 2H), 7.54-7.56 (m, 1H),
7.96-7.98 (m, 2H); 13C NMR (CDCl3, 150 MHz) δ 13.2, 25.4,
30.9, 34.0, 52.7, 52.8, 67.1, 127.9, 128.1, 128.5, 128.5, 132.9, 136.0,
137.5, 156.0, 171.4, 198.6, (1 masked aromatic); EIMS m/z 381
(M+, 5), 322 (20), 278 (30), 159 (40), 91 (100). Anal. Calcd for
C22H23O5N1: C, 69.28; H, 6.08; N, 3.67. Found: C, 69.28; H, 5.92;
N, 3.53.
(() (R)-Methyl 2-[(1S,2S,3R)-2-benzoyl-3-methylcyclopropyl]-
2-{[(benzyloxy)carbonyl]amino}ethanoate 26a: colorless solid;
mp 137-139 °C (CH2Cl2/hexane); Rf 0.36 (30% EtOAc in hexanes,
v/v); IR (nujol) 3320, 1753, 1694, 1648, 1539, 1224 cm-1; 1H NMR
(CDCl3, 600 MHz) δ 1.30 (d, J ) 6.0 Hz, 3H), 1.84-1.89 (m,
2H), 2.66 (dd, J ) 4.2, 4.2 Hz, 1H), 3.67 (s, 3H), 4.15 (dd, J )
9.0, 9.0 Hz, 1H), 5.12 (d, J ) 12.6 Hz, 1H), 5.14 (d, J ) 12.6 Hz,
1H), 5.37 (br d, J ) 9.0 Hz, 1H), 7.31-7.37 (m, 5H), 7.47-7.40
(m, 2H), 7.56-7.59 (m, 1H), 7.98-7.99 (m, 2H); 13C NMR (CDCl3,
150 MHz) δ 12.4, 23.8, 31.4, 32.0, 52.5, 52.9, 67.2, 128.0, 128.2,
General Procedure for the Synthesis of 1,2-Dioxines 8a-f.
A solution of the appropriate 1,3-butadiene (1 equiv) in anhydrous
dichloromethane (25 mL/g of 1,3-butadiene) was irradiated with
light from 3 × 500 W tungsten-halogen lamps at 0 °C in the
presence of rose bengal bis(triethylammonium) salt (0.01 equiv)
with oxygen bubbled through the solution for 6 h. The solution
was concentrated and the resulting residue purified by flash column
chromatography using 1:19 ethyl acetate/hexanes as elutent to yield
pure 1,2-dioxine 8. 1,2-Dioxines 8a,50 8b,50 8c,50 and 8d51have
previously been reported.
(()-{[(3R,6S)-3,6-Dihydro-6-phenyl-1,2-dioxin-3-yl]methoxy}-
(tert-butyl)dimethylsilane (8e): yield 1.55 g, 69%; colorless oil;
Rf 0.35 (50% CH2Cl2 in hexane, v/v); IR (neat) 2984, 2928, 2857,
1471, 1256, 1129, 837 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.09
(s, 3H), 0.09 (s, 3H), 0.91 (s, 9H), 3.80 (dd, J ) 5, 11 Hz, 1H),
3.99 (dd, J ) 7, 11 Hz, 1H), 4.55-4.61 (m, 1H), 5.59-5.61 (m,
1H), 6.09-6.18 (m, 2H), 7.36 (s, 5H); 13C NMR (75 MHz, CDCl3)
(50) Matsumoto, M.; Dobashi, S.; Kuroda, K.; Kondo, K. Tetrahedron
1985, 41, 2147-2154.
(51) Greatrex, B. W.; Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem.
2004, 69, 2580-2583.
(52) Palmer, F. Methodological Studies Directed Towards the Synthesis
of Diastereo- and Enantio-pure Cyclopropanes. Ph.D. dissertation, University
of Adelaide, 2000.
2638 J. Org. Chem., Vol. 73, No. 7, 2008

Concise Route to â-Cyclopropyl Amino Acids
128.5, 128.5, 133.0, 136.0, 137.5, 155.5, 172.0, 198.1 (1 masked
aromatic); EIMS m/z 381 (M+, 7), 322 (25), 278 (30), 230 (40),
91 (100). Anal. Calcd for C22H23O5N1: C, 69.28; H, 6.08; N, 3.67.
Found: C, 69.30; H, 6.03; N, 3.53.
2H), 2.81 (dd, J ) 4.8, 4.8 Hz, 1H), 3.81 (s, 3H), 4.25 (dd, J )
9.9, 8.7 Hz, 1H), 5.37 (br d, J ) 8.4 Hz, 1H), 7.42-7.47 (m, 2H),
7.53-7.58 (m, 1H), 8.00-8.02 (m, 2H); 13C NMR (CDCl3, 75
MHz) δ 13.2, 25.4, 28.2, 30.8, 35.1, 52.2, 52.6, 80.0, 128.2, 128.5,
132.9, 137.6, 155.4, 171.7, 199.0; EIMS m/z 347 (M+, 4), 188 (85),
159 (62), 105 (100), 77 (47); HRMS calcd for (M + Na+, ESIMS)
C19H25O5N1Na1 370.1630, found 370.1622.
(() (S)-Methyl 2-[(1S,2S,3R)-2-benzoyl-3-({[(tert-butyl)-1,1-
dimethylsilyl]oxy}methyl)cyclopropyl]-2-{[(benzyloxy)carbonyl]-
amino}ethanoate 25e: colorless oil; Rf 0.28 (20% EtOAc in
hexanes, v/v); IR (neat) 3334, 2953, 2929, 1747, 1723, 1669, 1522,
1452, 1253, 1050, 837 cm-1; 1H NMR (CDCl3, 200 MHz) δ 0.09
(s, 6H), 0.89 (s, 9H), 1.95-2.11 (m, 2H), 3.05 (dd, J ) 4.8, 4.8
Hz, 1H), 3.80 (s, 3H), 3.90-4.07 (m, 2H), 4.54 (dd, J ) 9.0, 8.6
Hz, 1H), 5.06 (d, J ) 11.9 Hz, 1H), 5.11 (d, J ) 11.9 Hz, 1H),
5.74 (d, J ) 8.6 Hz, 1H), 7.22-7.59 (m, 8H), 8.00-8.04 (m, 2H);
13C NMR (CDCl3, 50 MHz) -5.43, 18.1, 25.7, 27.2, 31.6, 52.5,
52.6, 60.5, 67.0, 127.9, 128.0, 128.2, 128.3, 128.4, 132.9, 136.1,
137.4, 155.8, 171.5, 198.3; EIMS m/z 511 (M+, 7), 496 (25), 454
(65), 105 (80), 91 (100); HRMS calcd for (M + Na+, ESI)
C28H37O6N1SiNa 534.2287, found 534.2284.
(()-(R)-Methyl 2-[(1S,2S,3R)-2-benzoyl-3-methylcyclopropyl]-
2-(tert-butoxycarbonylamino)ethanoate 28a: colorless solid; mp
152-153 °C; Rf 0.22 (7% diethyl ether in benzene, v/v); IR (Nujol)
3288, 1755, 1744, 1681, 1667, 1598, 1581, 1532, 1297, 1230 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.31 (d, J ) 6.0 Hz, 3H), 1.46 (s,
9H), 1.83-1.89 (m, 2H), 2.66 (d, J ) 4.5, 4.5 Hz, 1H), 3.68 (s,
3H), 4.07 (dd, J ) 8.4, 8.4 Hz, 1H), 5.21 (br d, J ) 8.1 Hz, 1H),
7.46-7.51 (m, 2H), 7.55-7.61 (m ,1H), 7.98-8.01 (m, 2H); 13C
NMR (CDCl3, 75 MHz) δ 12.4, 23.8, 28.2, 31.5, 32.2, 52.4, 80.2,
128.1, 128.5, 133.0, 137.5, 154.9, 172.4, 198.3. Anal. Calcd for
C19H25O5N1: C, 65.69; H, 7.25; N, 4.03. Found: C, 65.91; H, 7.34;
N, 4.15.
(() (R)-Methyl 2-[(1S,2S,3R)-2-benzoyl-3-({[(tert-butyl)-1,1-
dimethylsilyl]oxy}methyl)cyclopropyl]-2-{[(benzyloxy)carbonyl]-
amino}ethanoate 26e: colorless oil; Rf 0.25 (20% EtOAc in
hexanes, v/v); IR (neat) 3346, 2953, 2929, 2856, 1748, 1725, 1669,
1522, 1452, 1260, 1218 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.03
(s, 3H), 0.55 (s, 3H), 0.88 (s, 9H), 1.95-2.06 (m, 2H), 2.96 (dd, J
) 4.8, 4.8 Hz, 1H), 3.68 (s, 3H), 3.80 (dd, J ) 11.4, 6.3 Hz, 1H),
3.94 (dd, J ) 11.4, 5.1 Hz, 1H), 4.21 (dd, J ) 8.7, 6.9 Hz, 1H),
5.06-5.15 (m, 2H), 5.61 (d, J ) 6.9 Hz, 1H), 7.30-7.34 (m, 5H),
7.44-7.50 (m, 2H), 7.55-7.60 (m, 1H), 7.99-8.02 (m, 2H); 13C
NMR (CDCl3, 50 MHz) -5.48, -5.44, 18.1, 25.7, 27.3, 29.9, 30.0,
52.4, 53.1, 60.1, 67.0, 128.1, 128.1, 128.4, 128.5, 133.1, 136.0,
137.3, 155.6, 171.8, 197.7 (1 masked aromatic); EIMS m/z 511
(M+, 5), 495 (30), 453 (50), 105 (60), 91 (100); HRMS calcd for
(M + Na+, ESI) C28H37O6N1SiNa 534.2287, found 534.2283.
(()-(S)-Methyl 2-(tert-Butoxycarbonylamino)-2-{(1S,2R,3R)-
2-[(tert-butyldimethylsilyloxy)methyl]-3-(2-methoxybenzoyl)-
cyclopropyl}ethanoate 27f: colorless oil; Rf 0.56 (30% EtOAc in
hexanes, v/v); IR (neat) 3358, 1747, 1714, 1662, 1598, 1579, 1487,
1463, 1438, 1365, 1326, 1285, 1251 cm-1; 1H NMR (CDCl3, 600
MHz) δ 0.02 (s, 3H), 0.04 (s, 3H), 0.85 (s, 9H), 1.39 (s, 9H), 1.98-
2.02 (m, 2H), 2.90 (dd, J ) 4.8, 4.8 Hz, 1H), 3.75 (s, 3H), 3.84-
3.98 (m, 5H), 4.23 (dd, J ) 7.8, 7.8 Hz, 1H), 5.32 (br d, J ) 7.8
Hz, 1H), 6.95-7.00 (m, 2H), 7.42-7.45 (m, 1H), 7.57-7.59 (m,
1H); 13C NMR (CDCl3, 150 MHz) δ -5.42, -5.39, 18.1, 25.8,
28.3, 31.3, 31.5, 32.2, 52.2, 52.4, 55.6, 60.6, 79.9, 111.5, 120.7,
129.0, 130.1, 133.3, 155.2, 158.4, 172.3, 200.6; EIMS m/z 507 (M+,
<1), 450 (6), 394 (62), 350 (10), 333 (12), 216 (14), 135 (100), 57
(78). Anal. Calcd for C26H41O7Si1N1: C, 61.51; H, 8.14; N, 2.76.
Found: C, 61.73; H, 8.18; N, 2.62.
(() (R)-Methyl 2-(tert-butoxycarbonylamino)-2-{(1S,2R,3R)-
2-[(tert-butyldimethylsilyloxy)methyl]-3-(2-methoxybenzoyl)-
cyclopropyl}ethanoate 28f: colorless solid; mp 97-98 °C; Rf 0.45
(30% EtOAc in hexanes, v/v); IR (Nujol) 3385, 1749, 1713, 1651,
1598, 1257, 1209, 1157 cm-1; 1H NMR (CDCl3, 600 MHz) δ 0.038
(s, 3H), 0.043 (s, 3H), 0.87 (s, 9H), 1.41 (s, 9H), 1.95 (dddd, J )
9.0, 7.8, 5.4, 4.8 Hz, 1H), 2.02 (ddd, J ) 9.0, 9.0, 4.8 Hz, 1H),
2.95 (dd, J ) 4.8, 4.8 Hz, 1H), 3.61 (dd, J ) 9.6, 9.0 Hz, 1H),
3.66 (s, 3H), 3.89 (s, 3H), 3.93-3.96 (m ,2H), 5.39 (br s), 6.94-
6.98 (m, 2H), 7.42-7.45 (m, 1H), 7.57-7.58 (m, 1H); 13C NMR
(CDCl3, 150 MHz) δ -5.44, -5.41, 18.2, 25.9, 28.3, 29.7, 30.8,
31.8, 52.2, 53.5, 55.5, 60.7, 80.0, 111.6, 120.6, 128.6, 130.1, 133.5,
155.3, 158.6, 172.2, 199.8; EIMS m/z 507 (M+, <1), 450 (32),
394 (36), 350 (5), 319 (7), 135 (75), 57 (100). Anal. Calcd for
C26H41O7Si1N1: C, 61.51; H, 8.14; N, 2.76. Found: C, 61.46; H,
8.07; N, 2.65.
General Procedure for the Baeyer-Villiger Oxidation of
Cyclopropanes 25-28. A solution of cyclopropane in dichlo-
romethane (0.06 M) was added dropwise to trifluoroperacetic acid
[prepared by adding trifluoroacetic anhydride (275 equiv) to 30%
aqueous hydrogen peroxide (62.5 equiv) in dichloromethane (70
mL per gram of cyclopropane)]49 in dichloromethane at 0 °C,
maintaining the reaction temperature at 0 °C. The reaction was
allowed to stir (∼5-16 h) at 0 °C until complete (TLC), at which
time it was poured into a 2% aqueous potassium carbonate solution
and extracted with dichloromethane. The combined extracts were
washed with water, dried (MgSO4), filtered, and concentrated in
vacuo, and the crude cyclopropane (36 or 39) was purified by flash
column chromatography.
General Procedure for the Transesterification of Cyclopro-
panes 36 and 39. To a solution of cyclopropane in anhydrous
methanol (0.03 M) was added concd sulfuric acid (1 drop) and the
solution refluxed overnight. The volatiles were removed in vacuo,
and the crude cyclopropane (37 or 40) was purified by column
chromatography.
General Procedure for the Hydrolysis of Cyclopropanes 37
and 40.5 To a solution of cyclopropane in THF (0.035 M) was
added a 2.5 M solution of LiOH‚H2O (40 equiv) and the mixture
stirred overnight. Brine was added, the aqueous layer was washed
with ethyl acetate, and the aqueous layer was then acidified to pH
1 with 1 M HCl and extracted with ethyl acetate. The combined
organic fractions were dried (MgSO4), filtered, and concentrated
in vacuo to give cyclopropane (38 or 41).
(()-(1S,2S,3R)-Phenyl 2-[(S)-1-(benzyloxycarbonylamino]-2-
methoxy-2-oxoethyl)-3-methylcyclopropanecarboxylate 36a: yield
(351 mg, 76%); colorless oil; Rf 0.6 (30% EtOAc in hexanes, v/v);
1
IR (neat) 3335, 1731, 1715, 1694, 1593, 1331 cm-1; H NMR
(CDCl3, 300 MHz) δ 1.37 (d, J ) 5.7 Hz, 3H), 1.77-1.89 (m,
3H), 3.77 (s, 3H), 4.15 (dd, J ) 9.9, 8.7 Hz, 1H), 5.09 (d, J ) 12.0
Hz, 1H), 5.17 (d, J ) 12.0 Hz, 1H), 5.71 (br d, J ) 8.7 Hz, 1H),
7.04-7.06 (m, 2H), 7.17-7.37 (m, 8H); 13C NMR (CDCl3, 75
MHz) δ 12.8, 23.1, 25.9, 30.5, 52.3, 52.6, 67.1, 121.4, 125.7, 128.0,
128.1, 128.5, 129.2, 136.0, 150.5, 155.9, 171.5, 171.6; EIMS m/z
397 (M+, 1), 304 (21), 196 (23), 168 (17), 108 (15), 91 (100);
HRMS calcd for (M + Na+, ESI) C22H23O6N1Na 420.1423, found
420.1410.
(()-(1S,2S,3R)-Methyl 2-[(S)-1-(benzyloxycarbonylamino]-2-
methoxy-2-oxoethyl)-3-methylcyclopropanecarboxylate 37a: yield
(354 mg, 95%); colorless oil; Rf 0.5 (30% EtOAc in hexanes, v/v);
IR (neat) 3342, 1750, 1731, 1715, 1526, 1455, 1332 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.30 (d, J ) 5.4 Hz, 3H), 1.59-1.75 (m,
3H), 3.65 (s, 3H), 3.78 (s, 3H), 4.06 (dd, J ) 9.0, 9.0 Hz, 1H),
5.09 (d, J ) 12.0 Hz, 1H), 5.14 (d, J ) 12.0 Hz, 1H), 5.53 (br d,
J ) 9.0 Hz, 1H), 7.27-7.40 (m, 5H); 13C NMR (CDCl3, 75 MHz)
δ 12.8, 22.3, 25.8, 29.8, 51.9, 52.4, 52.6, 67.1, 128.1, 128.2, 128.5,
136.1, 155.8, 171.6, 173.6; EIMS m/z 335 (M+, 1), 276, (11), 232,
(()-(S)-Methyl 2-[(1S,2S,3R)-2-benzoyl-3-methylcyclopropyl]-
2-(tert-butoxycarbonylamino)ethanoate 27a: colorless solid; mp
100-101 °C; Rf 0.31 (7% diethyl ether in benzene, v/v); IR (Nujol)
1
3390, 1744, 1699, 1660, 1598, 1581, 1515, 1259, 1238 cm-1; H
NMR (CDCl3, 300 MHz) δ 1.39-1.50 (m, 12H), 1.88-1.92 (m,
J. Org. Chem, Vol. 73, No. 7, 2008 2639

Avery et al.
(11), 113 (52), 91 (100); HRMS calcd for (M + Na+, ESI)
C17H21O6N1Na 358.1267, found 358.1266.
(156 mg, 75%); colorless oil; Rf 0.4 (30% EtOAc in hexanes, v/v);
IR (neat) 3351, 1746, 1724, 1709, 1593, 1524, 1494, 1454, 1436,
1
1327 cm-1; H NMR (CDCl3, 300 MHz) δ 1.29 (d, J ) 5.7 Hz,
(()-(1S,2S,3R)-2-[(S)-(Benzyloxycarbonylamino)(carboxy)-
methyl]-3-methylcyclopropanecarboxylic Acid 38a: yield (289
mg, 98%); colorless solid; mp 201-202 °C; IR (Nujol) 3309, 3092,
3H), 1.68-1.86 (m, 3H), 3.81 (s, 3H), 4.06 (dd, J ) 8.7, 8.4 Hz,
1H), 5.08-5.17 (m, 2H), 5.46 (br d, J ) 8.4 Hz, 1H), 7.03-7.10
(m, 2H), 7.18-7.25 (m, 1H), 7.31-7.41 (m, 7H); 13C NMR (CDCl3,
75 MHz) δ 12.17, 21.8, 26.7, 29.4, 52.5, 52.7, 67.2, 121.4, 125.8,
128.1, 128.2, 128.5, 129.4, 136.0, 150.6, 155.5, 171.4, 172.1; EIMS
m/z 397 (M+, 3), 355 (8), 305, (42), 261 (15), 171 (16), 91 (100);
HRMS calcd for (M + Na+, ESI) C22H23O6N1Na 420.1423, found
420.1420.
1742, 1693, 1681, 1543, 1294, 1244 cm-1 1H NMR (CDCl3/
;
DMSO, 300 MHz) δ 1.31 (d, J ) 6.0 Hz, 3H), 1.55 (dd, J ) 4.2,
4.2 Hz, 1H), 1.65 (ddq, J ) 9.6, 6.0, 4.2 Hz, 1H), 1.76 (ddd, J )
9.6, 9.6. 4.2 Hz, 1H), 4.01 (dd, J ) 9.6, 9.6 Hz, 1H), 5.04-5.15
(m, 2H), 5.75 (br d, J ) 9.6 Hz, 1H), 7.28-7.36 (m, 5H), 10.91
(br s, 2H); 13C NMR (CDCl3/DMSO, 75 MHz) δ 12.8, 22.4, 25.9,
30.1, 52.3, 66.8, 127.87, 127.93, 128.4, 136.2, 155.9, 173.3, 176.1;
HRMS calcd for (M + Na+, ESI) C15H17O6N1Na 330.0954, found
330.0952.
(()-(1S,2S,3R)-Methyl 2-[(R)-1-(benzyloxycarbonylamino]-2-
methoxy-2-oxoethyl)-3-methylcyclopropanecarboxylate 40a: yield
(201 mg, 90%); colorless oil; Rf 0.3 (30% EtOAc in hexanes, v/v);
IR (neat) 3349, 1744, 1731, 1714, 1525, 1454, 1332, 1278, 1216
(()-(1S,2S,3R)-2-[(S)-Amino(carboxy)methyl]-3-methylcyclo-
propanecarboxylic Acid 2.6 To a solution of 38a (100 mg, 0.33
mmol) in methanol (7 mL) was added 10% Pd/C (18 mg) and the
mixture stirred overnight under an atmosphere of hydrogen. Water
(10 mL) was added and the solution filtered through Celite, washing
with water. The methanol was removed in vacuo and the aqueous
solution extracted with ethyl acetate. The aqueous layer was
evaporated to give amino acid 2: yield (56 mg, 99%); colorless
solid; dec 213 °C (lit.6 mp 178-180 °C); IR (solid) 3013, 2606,
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.20 (d, J ) 5.7 Hz, 3H),
1.52-1.71 (m, 3H), 3.66 (s, 3H), 3.76 (s, 3H), 3.96 (dd, J ) 9.0,
9.0 Hz, 1H), 5.45 (br d, J ) 9.0 Hz, 1H), 7.31-7.40 (m, 5H); 13
C
NMR (CDCl3, 75 MHz) δ 12.1, 21.0, 26.4, 28.5, 51.9, 52.5, 52.6,
67.1, 128.0, 128.2, 128.5, 136.0, 155.4, 172.1, 173.2; EIMS m/z
335 (M+, 31), 291 (59), 231 (100), 181 (56. Anal. Calcd for
C17H21O6N1: C, 60.89; H, 6.44; N, 4.18. Found: C, 61.02; H, 6.44;
N, 4.22.
1689, 1644, 1601, 1534, 1459, 1446, 1401, 1383, 1364, 1307 cm-1
;
1H NMR (D2O, 200 MHz) δ 1.26 (d, J ) 5.6 Hz, 3H), 1.52 (dd, J
) 4.6, 4.6 Hz, 1H), 1.64-1.84 (m, 2H), 3.42-3.54 (m, 1H); 13C
NMR (D2O, 75 MHz) δ 14.1, 24.6, 28.9, 29.8, 55.9, 175.3, 180.3.
Anal. Calcd for C7H11O4N1: C, 48.55; H, 6.40; N, 8.09. Found:
C, 48.40; H, 6.40; N, 8.00.
(()-(1S,2S,3R)-2-[(R)-(Benzyloxycarbonylamino)(carboxy)-
methyl]-3-methylcyclopropanecarboxylic acid 41a: yield (354
mg, 99%); colorless solid; mp 179-180 °C; IR (nujol) 3331, 1711,
1683, 1533, 1309, 1274, 1233 cm-1; 1H NMR (CDCl3, 300) δ 1.22
(d, J ) 5.7 Hz, 3H), 1.56-1.74 (m, 3H), 3.91 (dd, J ) 9.0, 8.4
Hz, 1H), 5.04-5.13 (m, 2H), 5.79 (br d, J ) 8.4 Hz, 1H), 7.25-
7.31 (m, 5H), 10.72 (br s, 2H); 13C NMR (CDCl3, 75 MHz) δ 12.0,
21.9, 26.6, 28.9, 52.5, 67.3, 128.1, 128.2, 128.5, 135.9, 155.8, 177.3,
179.2; EIMS m/z 307 (M+, 2), 289 (19), 218 (28), 153 (40), 127
(66), 44 (100). Anal. Calcd for C15H17O6N1: C, 58.63; H, 5.58; N,
4.56; Found: C, 58.58; H, 5.54; N, 4.60.
(()-(1S,2S,3R)-Methyl 2-[(S)-1-(benzyloxycarbonylamino)-2-
methoxy-2-oxoethyl]-3-phenylcyclopropanecarboxylate 37c: yield
(81 mg, 39% over two steps + 25c 27% recovered); colorless solid;
mp 106-107 °C; Rf 0.4 (30% EtOAc in hexanes, v/v); IR (neat)
3302, 1739, 1722, 1682, 1547, 1456, 1281 cm-1; 1H NMR (CDCl3,
300 MHz) δ 2.10 (ddd, J ) 9.6, 9.6, 4.8 Hz, 1H), 2.61 (dd, J )
4.8, 4.8 Hz, 1H), 2.93 (dd, J ) 9.6, 4.8 Hz, 1H), 3.61 (s, 3H), 3.73
(s, 3H), 3.89 (dd, J ) 9.6, 9.6 Hz, 1H), 5.09 (d, J ) 12.0 Hz, 1H),
5.14 (d, J ) 12.0 Hz, 1H), 5.51 (br d, J ) 9.6 Hz, 1H), 7.25-7.42
(m, 10H); 13C NMR (CDCl3, 75 MHz) δ 22.7, 31.8 (masked
carbon), 51.7, 52.1, 52.4, 67.1, 127.1, 128.0, 128.2, 128.3, 128.5,
128.6, 134.3, 136.1, 155.8, 171.1, 173.1. Anal. Calcd for
C22H23O6N1: C, 66.49; H, 5.83; N, 3.52. Found: C, 66.58; H, 5.87;
N, 3.45.
(()-(1S,2S,3R)-2-[(R)-Amino(carboxy)methyl]-3-methylcyclo-
propanecarboxylic Acid 42a. To a solution of 41a (110 mg, 0.36
mmol) in methanol (7 mL) was added 10% Pd/C (18 mg) and the
mixture stirred overnight under an atmosphere of hydrogen. Water
(10 mL) was added and the solution filtered through Celite, washing
with water. The methanol was removed in vacuo and the aqueous
solution extracted with ethyl acetate. The aqueous layer was
evaporated to give amino acid 42a: yield (59 mg, 95%); colorless
solid; dec 216 °C; IR (solid) 3054, 2587, 1682, 1604, 1511, 1401,
1359, 1332, 1240 cm-1; 1H NMR (D2O, 200 MHz) δ 1.24 (d, J )
(()-(1S,2S,3R)-2-[(S)-(Benzyloxycarbonylamino)(carboxy)-
methyl]-3-phenylcyclopropanecarboxylic acid 38c: yield (211
mg, 82%); colorless solid; mp 184-185 °C; IR (nujol) 3304, 3090,
1738, 1694, 1682, 1538, 1218, 1066 cm-1 1H NMR (CDCl3/
;
5.4 Hz, 3H), 1.63-1.79 (m, 3H), 3.44 (br d, J ) 9.8 Hz, 1H); 13
C
DMSO, 300) δ 2.15 (ddd, J ) 9.0, 9.0, 5.7 Hz, 1H), 2.50 (dd, J )
5.7, 5.7 Hz, 1H), 2.93 (dd, J ) 9.0, 5.7 Hz, 1H), 3.81 (dd, J ) 9.0,
9.0 Hz, 1H), 4.83-5.32 (m, 2H), 5.82 (br d, J ) 9.0 Hz, 1H),
7.16-7.44 (m, 5H), 10.55 (br s, 2H); 13C NMR (CDCl3/DMSO,
75 MHz) δ 22.7, 31.9 (masked carbon), 51.4, 66.6, 126.6, 127.7,
127.8, 128.0, 128.3, 128.8, 134.8, 136.1, 155.9, 172.5, 175.0. Anal.
Calcd for C20H19O6N1: C, 65.03; H, 5.18; N, 3.69; Found: C, 64.63;
H, 5.12; N, 3.69.
(()-(1S,2S,3R)-2-[(S)-Amino(carboxy)methyl]-3-phenylcyclo-
propanecarboxylic Acid 6.8 To a solution of 38c (81 mg, 0.22
mmol) in methanol (5 mL) was added 10% Pd/C (10 mg) and the
mixture stirred overnight under an atmosphere of hydrogen. Dilute
HCl solution (10 mL) was added and the mixture filtered through
Celite, washing with dilute HCl. The solution was taken to dryness
in vacuo, and then anhydrous methanol (2 mL) and propylene oxide
(5 mL) were added and the mixture stirred over night at ambient
temperature. The precipitated amino acid 6 was filtered, washed
with methanol, and dried in vacuo to give pure cyclopropane 6:
yield (43 mg, 83%); colorless solid; dec 200 °C (lit.8 mp 217-
218 °C). All data were consistent with that reported in the literature.8
(()-(1S,2S,3R)-Phenyl 2-[(R)-1-(benzyloxycarbonylamino]-2-
methoxy-2-oxoethyl)-3-methylcyclopropanecarboxylate 39a: yield
NMR (D2O, 75 MHz) δ 13.1, 22.9, 28.8, 29.4, 54.8, 175.8, 179.5.
Anal. Calcd for C7H11O4N1: C, 48.55; H, 6.40; N, 8.09. Found:
C, 48.27; H, 6.61; N, 7.79.
Acknowledgment. D.K.T., B.W.G., and T.D.A. thank the
Australian Research Council for funding. D.S.P. thanks Carls-
bergfondet, Direktør Ib Henriksens Fond, Brødrene Hartmanns
Fond, and Torben & Alice Frimodts Fond for funding.
Supporting Information Available: Experimental details for
compounds 25b, 26b, 25c, 26c, 25d, 26d, 31-35, 39b, 40b, 41b,
39c, 40c, 41c, 43, and 44b; 13C NMR spectra for compounds 8f,
25a, 26a,b, 26c, 25e, 26e, 27f, 28f, 27a, 28a, 31-34, 36a, 38a, 2,
38c, 39a, 40a, 41a, 42a, 39b, 40b, 41b, 40c, 41c, 43, and 44b;
1
and H NMR spectra for compounds 8e, 25b-d, 26d, 35, 37a,c,
and 39c. Crystallographic data and CIF files for 26a, 26b, 27a, 6,
25d, 27f, and 28f. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO7024256
2640 J. Org. Chem., Vol. 73, No. 7, 2008