Synthesis of γ,δ-Unsaturated and δ,ε-Unsaturated α-Amino Acids from Fragmentation of γ- and δ-Lactones

Article abstract of DOI:10.1021/jo035401m

A noncoded amino acid of cyclomarin A (1) was synthesized in a racemic fashion. The method employs a six-membered ring template to control the relative stereochemistry and introduction of the functional groups. Ultimately, Pd-catalyzed fragmentation of the lactone provided γ-δ-unsaturated and δ,ε-unsaturated α-amino acids. A Pd-catalyzed ring opening of a γ-lactone is also reported.

Full text of DOI:10.1021/jo035401m

Syn th esis of γ,δ-Un sa tu r a ted a n d δ,E-Un sa tu r a ted r-Am in o Acid s
fr om F r a gm en ta tion of γ- a n d δ-La cton es
†
J ames E. Tarver, J r. and Madeleine M. J oulli e´ *
Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
Philadelphia, Pennsylvania 19104-6323, and Medicinal Chemistry, Lexicon Pharmaceuticals,
3
50 Carter Road, Princeton, New J ersey 08450
mjoullie@sas.upenn.edu
Received September 24, 2003
A noncoded amino acid of cyclomarin A (1) was synthesized in a racemic fashion. The method
employs a six-membered ring template to control the relative stereochemistry and introduction of
the functional groups. Ultimately, Pd-catalyzed fragmentation of the lactone provided γ,δ-
unsaturated and δ,ꢀ-unsaturated R-amino acids. A Pd-catalyzed ring opening of a γ-lactone is also
reported.
-5
In tr od u ction
R-amino acids,3 and Bartlett has published extensively
on the synthesis of γ,δ-unsaturated lactic acid deriva-
Unusual amino acids as constituents of natural prod-
ucts provide a classic example of nature’s ingenuity in
structural modification. These unique structures also
present a prolific source of challenges to existing and
evolving synthetic methods. Although amino acid syn-
thesis has received much attention from the synthetic
organic community, it remains an important problem.
The development of efficient methods by either extending
the scope of existing methods or developing new strate-
gies for synthesizing these compounds is an ongoing effort
in our laboratories. Although there are methods in the
literature for the synthesis of γ,δ-unsaturated R-amino
acids, there is no general method for synthesizing δ,ꢀ-
unsaturated R-amino acids. Our interest in these sub-
strates originated from (2S,3R)-2-amino-3,5-dimethylhex-
6,7
tives
using similar methods. However, none of the
literature examples possessed a degree of steric hin-
drance equivalent to that of our target. Thus, the chal-
lenge in applying this strategy was the development of
a convenient synthesis of the requisite ester. Recent
methods investigated for the esterification of tertiary
8
alcohols have included the use of phase-transfer reagents
or zinc-mediated activation of acid chlorides; ScOTf
9
3
/
10
DMAP treatment of N-hydroxysuccinimide esters; reac-
tion with MgBr , tertiary amines, and the appropriate
anhydrides; and the use of Ce(OTf) with carboxylic
2
11
4
12
acids. Unfortunately, none of these methods proved to
satisfactorily effect acylation of the requisite tertiary
allylic alcohol.
As an alternative to the [3,3] sigmatropic rearrange-
ment, a fragmentation strategy was undertaken to install
the olefin functionality. In this strategy (Figure 2), the
six-membered ring template would be employed to control
the relative stereochemistry of the 2-amino and 3-methyl
groups, as well as to mask the carboxylic acid functional-
ity as the lactone. This approach would allow for signifi-
cant flexibility in the introduction of the amino group,
as a number of methods are available for the function-
alization of esters at the R-position. To explore the
4
-enoic (2), a nonproteinogenic amino acid contained in
the potent anti-inflammatory agent cyclomarin A (1)
1
(
Figure 1). Prior to the initiation of this project, this
noncoded amino acid had not been previously synthe-
sized. Recently, a synthesis of 2 from Boc-L-Asp(OBzl)-
OH was reported. However, there still remained a need
for more general methods of synthesizing amino acid
compounds with high functional group density and
potential for improvement in the efficiency of the previous
synthesis.
2
(
3) Kazmaier, U.; Krebs, A. Angew. Chem., Int. Ed. Engl. 1995, 34,
012-2014.
4) Kazmaier, U.; Maier, S. J . Chem. Soc., Chem. Commun. 1995,
2
1
Resu lts a n d Discu ssion
(
991-1992.
An obvious disconnection for 2-amino-3,5-dimethylhex-
(5) Kazmaier, U.; Krebs, A. Tetrahedron Lett. 1999, 40, 479-482.
(6) Bartlett, P. A.; Tanzella, D. J .; Barstow, J . F. J . Org. Chem. 1982,
4
-enoic acid (2) is the retro-Claisen rearrangement
4
7, 3941-3945.
7) Bartlett, P. A.; Barstow, J . F. J . Org. Chem. 1982, 47, 3933-
3941.
(Figure 2). Kazmaier and co-workers reported on the ease
(
of this reaction in the synthesis of γ,δ-unsaturated
(
8) Szeja, W. Synthesis 1980, 402-403.
(
9) Yadav, J . S.; Reddy, G. S.; Srinivas, D.; Himabindu, K. Synth.
†
Lexicon Pharmaceuticals.
Comm. 1998, 28, 2337-2342.
(1) Renner, M. K.; Shen, Y.-C.; Cheng, X.-C.; J ensen, P. R.; Frank-
(10) Zhao, H.; Pendri, A.; Greenwald, R. B. J . Org. Chem. 1998, 63,
7559-7562.
moelle, W.; Kauffman, C. A.; Fenical, W.; Lobkovsky, E.; Clardy, J . J .
Am. Chem. Soc. 1999, 121, 11273-11276.
(11) Vedejs, E.; Daugulis, O. J . Org. Chem. 1996, 61, 5702-5703.
(12) Iranpoor, N.; Shekarriz, M. Bull. Chem. Soc. J pn. 1999, 72,
455-458.
(2) Sugiyama, H.; Shioiri, T.; Yokokawa, F. Tetrahedron Lett. 2002,
4
3, 3489-3492.
1
0.1021/jo035401m CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/07/2004
J . Org. Chem. 2004, 69, 815-820
815

Tarver and J oullie´
F IGURE 1. Cyclomarin A (1) and its noncoded amino acids.
To remove the possibility of hydroxyl group interfer-
ence in further manipulations, alcohol 5 was converted
to its TBS ether. This reaction led to the production of
two compounds that were inseparable by flash chroma-
tography; the desired TBS ether 6 and the TBS ether 7
(in which the olefin had isomerized out of conjugation)
were isolated as a 3:1 mixture in 65% yield. The driving
force for this isomerization may be the relief of strain
energy generated in the product. Examination of a crude
model supported this hypothesis, as the exo-methylene
compound 7 was found to be 1.05 kcal/mol more stable
than 6 by MM2 minimized energy calculations (Figure
4
). This proclivity for isomerization indicated that an
F IGURE 2. Retro-Claisen rearrangement and fragmentation
strategies.
alternative method for functionalization of the R-center
would be necessary.
The alternative strategy was designed to utilize the
same epoxyketone precursor but to employ a Knoevenagel
condensation to avoid the issue of E/ Z selectivity. It was
believed that lactonization should proceed in a similar
fashion with concomitant hydrolysis and decarboxylation
of the nonparticipating ester. It is worth noting that the
most effective and general method reported in the
literature for achieving the condensation reaction of
malonic esters with ketone substrates requires use of
feasibility of this method, we chose to examine the
racemic synthesis of this amino acid.
The 5-hydroxy-4,6,6-trimethyl-5,6-dihydropyran-2-one
(
5) could be readily synthesized from commercially avail-
1
3
able mesityl oxide in three steps. A modification of this
procedure was employed to generate this ene-lactol.
Mesityl oxide was treated with basic peroxide14 to afford
the R,â-epoxyketone 3 (Scheme 1), a system that is known
to be a powerful synthetic building block.15
1
7
TiCl
4
and pyridine, as described by Lehnert. Other
The desired Z-olefin was prepared with the Horner-
Emmons reagent in 1,4-dioxane, as previously de-
scribed,13 affording a 1:4 mixture of E- and Z-olefins,
respectively, in 91% yield. Separation of the two isomers
proved unnecessary, for when the mixture was treated
examples of this methodology have been primarily re-
stricted to cyclohexanones.1
8,19
This dehydration reaction
has also been effected on acetophenones using a combi-
nation of acetic acid and various acetate salts with
malonates.2
0,21
Other successful conditions have been
with either 60% HClO
4
in EtOH16 or triflic acid in
reported employing dibromomalonates with reductive
dichloromethane, cyclization to the desired δ-lactone 5
was effected in 67% and 96% yields, respectively. The
presumed diol side product was easily removed by column
chromatography. Thus, the synthesis of lactone 5 was
achieved in 76% yield over three steps.
2
2
tributyl antimony with a variety of cyclohexanones, but
again the scope of this methodology was limited to
cyclohexanones.2
2,23
Unfortunately, all attempts to effect
the Knoevenagel condensation on the epoxy ketone or
mesityl oxide using any of the above methods were
unsuccessful.
We believed that the most energetically favorable
lactone conformation would position the hydroxyl group
in a pseudoaxial orientation in order to minimize A1
strain with the vinylic methyl group, as this group would
be required to facilitate the orbital alignment necessary
for the elimination (Figure 3).
,3
(
(
17) Lehnert, W. Tetrahedron 1973, 29, 635-638.
18) Iio, H.; Isobe, M.; Kawai, T.; Goto, T. J . Am. Chem. Soc. 1979,
101, 6076-6080.
19) Ghera, E.; Maurya, R.; Ben-David, Y. J . Org. Chem. 1988, 53,
912-1918.
20) Erian, A. W.; Araki, V. F.; Aziz, S. I.; Sherif, S. M. Monatsh.
(
1
(
(
13) Bardili, B.; Marschall-Weyerstahl, H.; Weyerstahl, P. Liebigs
Ann. Chem. 1985, 275-300.
14) Wasson, R. L.; House, H. O. Organic Syntheses; Wiley: New
Chem. 1999, 130, 661-669.
(21) Davis, A. P.; Egan, T. J .; Orchard, M. G.; Cunningham, D.;
McArdle, P. Tetrahedron 1992, 48, 8725-8738.
(22) Davis, A. P.; Bhattarai, K. M. Tetrahedron 1995, 51, 8033-
8042.
(
York, 1963; Collect. Vol. IV, pp 552-553.
(
(
15) Lauret, C. Tetrahedron: Asymmetry 2001, 12, 2359-2383.
16) Wei-Shan, Z.; Hui-Quiang, Z.; Zhi-Qin, W. J . Chem. Soc., Perkin
(23) Bhattarai, K. M.; Davis, A. P.; Perry, J . J .; Walter, C. J .; Menzer,
S.; Williams, D. J . J . Org. Chem. 1997, 62, 8463-8473.
Trans. 1 1990, 2281-2285.
8
16 J . Org. Chem., Vol. 69, No. 3, 2004

γ,δ- and δ,ꢀ-Unsaturated R-Amino Acids
SCHEME 1
ethers 6 and 7 led to predominantly the cis-substituted
saturated TBS ether 8, along with a trace amount of the
trans-product (Scheme 3) as determined by comparison
of coupling constants for the tosylate series. Treatment
of this lactone with Evans’ modified azide transfer
F IGURE 3. Effect of A1,3 strain in the lactone.
25
conditions for esters, which include inverse addition of
the potassium enolate to trisyl azide followed by an acetic
acid quench with extended stirring at room temperature
for 15 h, yielded the desired azido-lactone 9 in 63% yield.
The azide was reduced using hydrogen and catalytic
palladium on carbon, and the subsequent amine was
trapped as its tert-butyl carbamate. The hydroxyl group
was liberated by cleavage of the silyl ether with tetrabu-
tylammonium fluoride buffered with acetic acid, produc-
ing alcohol 11 in 84% yield, presumably by simultaneous
rearrangement of the initially formed lactone 10. The
structure and relative stereochemistry of alcohol 11 were
verified by X-ray crystal diffraction.
F IGURE 4. Energy barrier to isomerization.
SCHEME 2
With the hydroxyl group in the side chain rather than
the ring in 1l in an exocyclic position, the outlook for the
proposed ring opening improved, as free rotation would
remove the rigid alignment requirement necessary for
reductive fragmentation. In an attempt to install a
reductive handle, alcohol 11 was treated with methane-
sulfonyl chloride and triethylamine, but neither the
mesylate nor the chloride was obtained. As we might
have expected, elimination product 12 was formed in good
yield.
We believed that ring opening of such a system could
be achieved by taking advantage of the nucleophilic
nature of palladium(0) with allylic acetoxy groups. In this
substrate, a hydride would be required for displacement
of the intermediate (π-allyl)palladium complex. The use
of polymethylhydrosiloxane (PMHS)26 as a mild hydride
donor for the displacement of allylic acetates has been
reported.27 However, the regioselectivity of the reduction
of allylic acetates of disubstituted olefins was not predict-
able. Lautens and co-workers employed palladium-
catalyzed formate reduction of allylic acetates in con-
junction with ring-closing olefin metathesis substrates
but also observed competitive â-hydride elimination,
resulting in diene formation.28 Mikami and co-workers
reported the reduction of allylic acetates and phosphates
After considering the limitations of the Knoevenagel
condensation strategy, we revisited the original approach,
focusing our efforts on circumvention of the strain
inherent in the cyclohexenone system (Scheme 2).
To this end, ene-lactol 5 was reduced by hydrogenation
with palladium on carbon to give the saturated lactol as
a racemic mixture of cis- and trans-isomers. The alcohols
were protected as both TBS ethers and tosylates. The
tosylates proved separable, and their stereochemistry
was determined by X-ray crystal diffraction. These
protected alcohols were then treated with a variety of
azide transfer conditions, including LiHMDS and 2,4,6-
triisopropylbenzenesulfonyl azide (trisyl azide), followed
by an acetic acid quench.24 However, all conditions
investigated led to complex mixtures.
using a SmI
2
-Pd(PPh
3 4
) system in which regioselectivity
was drastically affected by the proton source that was
Further examination of the olefin reduction revealed
that hydrogenation of the 3:1 mixture of allylic TBS
(
25) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011-4030.
(
26) Lipowitz, J .; Bowman, S. A. J . Org. Chem. 1973, 38, 162-165.
(24) Hanessian, S.; Moitessier, N.; Wilmouth, S. Tetrahedron 2000,
(27) Keinan, E.; Greenspoon, N. J . Org. Chem. 1983, 48, 3545-3548.
(28) Hughes, G.; Lautens, M.; Wen, C. Org. Lett. 2000, 2, 107-110.
5
6, 7643-7660.
J . Org. Chem, Vol. 69, No. 3, 2004 817

Tarver and J oullie´
SCHEME 3
SCHEME 4
received very little attention to date. Treatment of 12
with sodium borohydride in the presence of palladium
catalysis and in the absence of catalyst provided different
results. As expected, reduction with NaBH
catalyst resulted in quantitative formation of aminodiol
4. However, when NaBH was used in conjunction with
Ph P) Pd in THF, a mixture of compounds 13 and 2 was
4
without
1
4
(
3
3
obtained in a 2:3 ratio in favor of the desired olefin and
the total yield was improved to 58%. The diol 14 was also
produced in 4% yield.
Con clu sion s
Racemic syntheses of the 2-amino-3,5-dimethylhex-4-
enoic acid and 2-amino-3,5-dimethylhex-5-enoic acid were
accomplished. This strategy complements the existing
methods in the literature for synthesizing γ,δ-unsatur-
ated amino acid substrates with steric demand or disub-
stitution at the δ-position. A new method for the syn-
thesis of δ,ꢀ-unsaturated amino acids is reported. The
palladium-catalyzed reduction of allylic γ-lactone 12 with
a variety of hydride sources represents one of the few
examples of this type of reaction.
employed.29 Hutchins and co-workers reported reduction
of allylic acetates with palladium(0) and NaBH
NaBH
CN30 and of various allylic oxgen, sulfur, and
selenium functional groups with Pd(PPh and LiBH-
In this account, the authors suggested that poorer
hydride transfer reagents such as NaBH or NaBH CN
4
or
3
3 4
)
3
1
3
Et .
4
3
tend to attack the π-allyl system at the most electrophilic
carbon, whereas potent hydride sources attack the carbon
with greater steric accessibility to give the more highly
substituted olefin products.31 However, ammonium for-
mate was exceptional in that it consistently provided the
less-substituted olefin regardless of substrate.
Exp er im en ta l Section
Gen er a l Meth od s.32 5-Hyd r oxy-4,6,6-tr im eth yl-5,6-d i-
h yd r op yr a n -2-on e13 (5). Method A: To a cold (0 °C) solution
of enoate E/ Z-4 (3.0 g, 16.3 mmol) in HPLC EtOH (410 mL)
In the case of substrate 12, reductive ring opening
using strong hydride sources such as LAH or LiBHEt
3
4
was added 60% HClO (45 mL, 0.41 mol) dropwise via an
was not feasible because of the lability of the lactone.
Reactions employing the ammonium formate also seemed
unsuitable as the terminal olefin would likely be regener-
ated following ring fragmentation. Therefore, we chose
addition funnel over 20 min at 0 °C. After addition, the
reaction was warmed to room temperature for 20 min and then
cooled back to 0 °C to neutralize it with 4 N NaOH (100 mL).
The reaction was concentrated in vacuo, then diluted with
water (150 mL), and extracted with CH
combined organic phases were washed with brine until neu-
tral, dried (Na SO ), and concentrated. Purification by column
chromatography (EtOAc-hexanes) yielded 5 as a yellow oil
1.37 g, 67%). Method B: To a cold (-40 °C) solution of enoate
2
Cl
2
(2 × 250 mL). The
4
to proceed with the PMHS/NaBH system in the belief it
might provide us with the more thermodynamically
stable trisubstituted olefin 2. We expected conversion to
be a challenging issue in this case because of the
favorable reversibility of the ring-closing event with the
2
4
(
E/ Z-4 (3.00 g, 16.3 mmol) in CH Cl (140 mL) was added CF -
2
2
3
(
π-allyl)palladium intermediate (Scheme 4).
SO
3
H (1.44 mL, 16.3 mmol) in CH
2
Cl
2
(40 mL) dropwise via
an addition funnel. The reaction was stirred at -40 °C for 1 h
Treatment of 12 with (Ph P) Pd and PMHS success-
3
4
and then warmed to -20 °C for 1 h. When starting material
fully liberated the carboxylate ion, but hydride displace-
ment of the palladium complex afforded the less-
substituted olefin as the major product in low yield (35%).
The product mixture revealed a 2.6:1 ratio of terminal
olefin 13 and olefin 2, as well as a significant quantity
of starting material. This type of lactone opening has
3
had disappeared as shown by TLC, 5%NaHCO solution (50
mL) was added to quench the reaction at -20 °C. The layers
were separated, the aqueous layer was extracted with CH Cl
2
2
(2 × 100 mL), and the combined organic phase was dried (Na -
2
4
SO ) and concentrated to a yellow oil (2.94 g). The crude oil
was purified by column chromatography (EtOAc-hexanes) to
yield 5 as a yellow oil (1.95 g, 96%): R 0.11 (30:70 EtOAc-
) δ 1.39 (s, 3H), 1.44 (s,
f
1
hexanes); H NMR (500 MHz, CDCl
H), 2.06 (s, 3H), 3.86 (s, 1H), 5.81 (s, 1H); C NMR (125 MHz,
3
(
29) Yoshida, A.; Hanamoto, T.; Inanaga, J .; Mikami, K. Tetrahedron
Lett. 1998, 39, 1777-1780.
30) Hutchins, R. O.; Learn, K.; Fulton, R. P. Tetrahedron Lett. 1980,
1, 27-30.
31) Hutchins, R. O.; Learn, K. J . Org. Chem. 1982, 47, 4380-4382.
13
3
(
2
(32) Tarver, J . E.; Pfizenmayer, A. J .; J oulli e´ , M. M. J . Org. Chem.
2001, 66, 7575-7587.
(
8
18 J . Org. Chem., Vol. 69, No. 3, 2004

γ,δ- and δ,ꢀ-Unsaturated R-Amino Acids
CDCl
IR (neat) 3406 (br), 2924 (m), 2900 (w), 2853 (w), 1715 (s),
657 (w), 1443 (w), 1378 (m), 1298 (m), 1154 (s), 990 (m), 792
3
) δ 20.4, 22.2, 25.9, 71.5, 82.8, 116.2, 157.8, 164.3;
(s, 9H), 1.13 (d, J ) 6.6 Hz, 3H), 1.35 (s, 3H), 1.37 (s, 3H),
2.11-2.26 (m, 1H), 3.56 (d, J ) 1.7 Hz, 1H), 3.90 (d, J ) 11.4
1
Hz, 1H); 13C NMR (125 MHz, CDCl
3
) δ -3.5, -3.4, 16.5, 18.4,
-
1
(w) cm
.
26.1, 26.3, 27.8, 35.1, 60.5, 75.0, 85.6, 168.9; IR (neat) 2954
(
8
m), 2931 (m), 2112 (s), 1776 (w), 1735 (s), 1261 (s), 1110 (s),
5
-(ter t-Bu tyld im eth ylsila n yloxy)-4,6,6-tr im eth yl-5,6-d i-
-
1
27 3 3
34 (m), 777 (m) cm ; HRMS m/z calculated for C14H N O -
h yd r op yr a n -2-on e (6) a n d 5-(ter t-Bu tyld im eth ylsila n yl-
oxy)-6,6-dim eth yl-4-m eth ylen e-tetr ah ydr opyr an -2-on e (7).
To a cold (-20 °C) solution of alcohol 5 (1.18 g, 7.56 mmol)
and 2,6-lutidine (1.8 mL, 15.1 mmol) in CH Cl (8 mL) was
2 2
added TBDMSOTf (2.1 mL, 9.10 mmol) dropwise via a syringe
over 20 min. The reaction was stirred 25 min more before being
+
SiNa (M + Na) 336.1719, found 336.1736.
[5-(ter t-Bu t yld im et h ylsila n yloxy)-4,6,6-t r im et h yl-2-
oxotetr a h yd r op yr a n -3-yl]ca r ba m ic Acid ter t-Bu tyl Ester
(10). A flask containing a solution of azide 9 (0.203 g, 0.648
mmol), 10% Pd/C (52 mg), and Boc
HPLC EtOAc (10 mL) was evacuated and then fitted with a
balloon of H . The reaction was stirred for 12 h, and the
2
O (0.204 g, 0.933 mmol) in
quenched with saturated NaHCO
room temperature, and poured into saturated NaHCO
mL). The mixture was shaken, and the layers were allowed to
separate. The aqueous layer was extracted with Et
O (3 × 50
mL), and the combined organic phase was washed with 1 N
SO ) and
3
(3 mL), then warmed to
3
(40
2
palladium was removed by filtration. The filtrate was concen-
trated to a white solid. The crude solid was purified by column
chromatography (petroleum ether to 20:80 EtOAc-petroleum
ether) to give 10 as a white solid (0.236 g, 94%): mp 152-153
2
HCl (2 × 80 mL). The organic phase was dried (Na
2
4
0.21 (20:80 EtOAc-petroleum ether); 1H NMR (500
concentrated to a white solid. Purification by column chroma-
°C; R
MHz, CDCl ) δ 0.09 (s, 3H), 0.11 (s, 3H), 0.92 (s, 9H), 1.07 (d,
f
tography (EtOAc-petroleum ether) yielded a white powder
1.33 g, 65%) as an inseparable 3:1 mixture of allylic TBDMS
ethers 6 and 7. Data for 6: H NMR (500 MHz, CDCl
3
(
J ) 6.7 Hz, 3H), 1.37 (s, 3H), 1.43 (s, 9H), 1.47 (s, 3H), 2.60-
1
3
) δ 0.12
2.80 (m, 1H), 3.63 (d, J ) 2.0 Hz, 1H), 3.77-3.98 (m, 1H),
4.83-5.03 (m, 1H); 13C NMR (125 MHz, CDCl
) δ -4.7, -4.1,
(
2
s, 3H), 0.17 (s, 3H), 0.95 (s, 9H), 1.38 (s, 3H), 1.43 (s, 3H),
3
.00 (s, 3H), 4.19 (s, 1H), 5.82 (s,1H); 13C NMR (125 MHz,
) δ -4.1, -3.8, 20.5, 21.3, 26.8, 73.3, 82.8, 116.5, 158.1,
69.1; IR (neat) 2927 (w), 2854 (w), 1711 (s), 1655 (w), 1472
w), 1366 (w), 1310 (w), 1293 (w), 1252 (w), 1161 (m), 1071
9.8, 18.1, 25.8, 28.3, 29.7, 30.3, 36.6, 53.0, f) 74.9, 80.0, 86.9,
155.4, 169.9; IR (neat) 3409 (br), 2931 (m), 2856 (w), 1732 (s),
1715 (s), 1504 (m), 1366 (m), 1254 (s), 1159 (s), 1108 (s), 1043
CDCl
3
1
(
(
-
1
37
(s), 833 (m), 776 (m) cm ; HRMS m/z calculated for C19H -
NO SiNa (M + Na) 410.2339, found 410.2338.
5
-
1
+
w), 994 (m), 836 (m), 776 (m), 603 (w) cm ; HRMS m/z
calculated for C14
93.1537. Data for 7: H NMR (500 MHz, CDCl
H), 0.14 (s, 3H), 0.93 (s, 9H), 1.33 (s, 3H), 1.40 (s, 3H), 3.22
+
H
26
O
3
SiNa (M + Na) 293.1549, found
[5-(1-Hyd r oxy-1-m eth yleth yl)-4-m eth yl-2-oxotetr a h y-
d r ofu r a n -3-yl]ca r ba m ic Acid ter t-Bu tyl Ester (11). To a
solution of TBDMS ether 10 (0.251 g, 0.648 mmol) in THF (6.4
mL) was added a 1.0 M TBAF solution in THF (1.8 mL) and
acetic acid (0.02 mL). The reaction was stirred for 48 h and
concentrated to dryness. Column chromatography (30:70
EtOAc-petroleum ether to 100% EtOAc) afforded 11 as a
f
1
2
3
(
3
) δ 0.08 (s,
doublet of triplets, J ) 18.7, 1.3 Hz, 1H), 3.45 (doublet of
triplets, J ) 17.8, 2.2 Hz, 1H), 4.00 (s, 1H), 5.06 (d, J ) 0.5
1
3
3
Hz, 1H), 5.12 (d, J ) 1.0 Hz, 1H); C NMR (125 MHz, CDCl )
δ -5.1, -4.6, 18.1, 23.7, 35.2, 75.6, 83.7, 112.6, 139.3, 163.3;
IR (neat) 2927 (w), 2854 (w), 1711 (s), 1655 (w), 1472 (w), 1366
white solid (0.149 g, 84%): mp 165-166 °C; R 0.41 (50:50
1
(
8
C
w), 1310 (w), 1293 (w), 1252 (w), 1161 (m), 1071 (w), 994 (m),
36 (m), 776 (m), 603 (w) cm ; HRMS m/z calculated for
EtOAc-hexanes); H NMR (500 MHz, CDCl ) δ 1.23 (s, 3H),
3
-
1
1.31 (d, J ) 6.6 Hz, 3H), 1.33 (s, 3H), 1.45 (s, 9H), 1.88 (brs,
+
14
H
26
O
3
SiNa (M + Na) 293.1549, found 293.1537.
1H), 2.33-2.49 (m, 1H), 3.87 (d, J ) 8.6 Hz, 1H), 4.04-4.20
(m,1H), 4.84-5.09 (m, 1H); 13C NMR (125 MHz, CDCl
) δ 17.6,
cis-5-(ter t-Bu t yld im et h ylsila n yloxy)-4,6,6-t r im et h yl-
3
tetr a h yd r op yr a n -2-on e (8). The 3:1 mixture of TBDMS
ethers 6 and 7 (1.16 g, 4.29 mmol) was dissolved in absolute
EtOH (25 mL), 10% Pd/C (225 mg) was added, and the mixture
was stirred under a hydrogen atmosphere. After 22 h, the
reaction mixture was filtered through a slurry of Celite, and
EtOH was evaporated to dryness to obtain 8 as a white powder
1.18 g, 100%), which was used without further purification:
mp 82-84 °C; R
0.24 (30:70 EtOAc-petroleum ether); 1
NMR (500 MHz, CDCl ) δ 0.06 (s, 6H), 0.88 (s, 9H), 0.97 (d,
J ) 6.1 Hz, 3H), 1.33 (s, 6H), 2.21-2.41 (m, 3H), 3.49 (s,1 H);
25.0, 27.1, 28.3, 37.9, 57.8, 71.1, 80.4, 89.0, 155.7, 174.4; IR
(neat) 3455 (w, br), 3277 (m), 2974 (w), 1788 (s), 1713 (s), 1362
-
1
(w), 1172 (m) cm ; HRMS (CI) m/z calculated for C13
(M + H) 274.1654, found 274.1652.
H
23NO
5
+
(5-Isop r op en yl-4-m et h yl-2-oxot et r a h yd r ofu r a n -3-yl)-
ca r ba m ic Acid ter t-Bu tyl Ester (12). To a an ice-cooled
solution of alcohol 11 (473 mg, 1.74 mmol) and triethylamine
(2.9 mL, 20.9 mmol) in CH Cl (0.5 mL) was added methane-
sulfonyl chloride (1.3 mL, 17.4 mmol) followed by DMAP (212
mg, 1.74 mmol). The reaction was warmed to room tempera-
ture and stirred for 48 h. The reaction was diluted with CH2-
Cl and washed with 10% HCl, saturated NaHCO solution,
and brine. The organic phase was dried (Na
trated. The crude residue was purified by column chromatog-
raphy (EtOAc-hexanes) to afford 12 as a clear foam (282 mg,
6
CDCl
2
4
CDCl
1
1
(
f
H
2
2
3
1
3
C NMR (125 MHz, CDCl
6.6, 27.9, 28.5, 28.9, 32.2, 73.8, 85.1, 170.9; IR (neat) 2935
m), 2855 (m), 1706 (s), 1472 (w), 1301 (s), 1136 (s), 775 (s)
3
) δ -3.6, -3.4, 18.1, 18.3 25.9, 26.0,
2
(
2
3
2
SO
4
) and concen-
-
1
+
cm ; HRMS m/z calculated for C14
95.1705, found 295.1705.
-Azid o-5-(ter t-bu tyld im eth ylsila n yloxy)-4,6,6-tr im eth -
H
28
O
3
SiNa (M + Na)
2
3%); R
f
0.73 (50:50 EtOAc-hexanes); 1H NMR (500 MHz,
3
) δ 1.17 (d, J ) 6.5 Hz, 3H), 1.44 (s, 9H), 1.74 (s, 3H),
.13-2.28 (m, 1H), 4.14 (brs, 1H), 4.34 (d, J ) 10.1 Hz, 1H),
.49 (m, 1H), 5.05 (s, 1H), 5.06 (s, 1H); 13C NMR (125 MHz,
) δ 14.3, 16.6, 28.2, 42.3, 57.5, 80.5, 86.7, 116.3, 139.5,
55.5, 174.2; IR (neat) 3338 (br), 2974 (w), 2930 (w), 1791 (s),
yltetr a h yd r op yr a n -2-on e (9). To a 0.5 M KHMDS solution
in toluene (4.4 mL, 2.22 mmol) cooled to -78 °C was added
lactone 8 (0.550 g, 2.02 mmol) in THF (9 mL) dropwise via a
syringe. The reaction was stirred at -78 °C for 0.5 h and then
transferred via a cannula to a cold (-78 °C) solution of 2,4,6-
triisopropylbenzenesulfonyl azide (0.781 g, 2.53 mmol) in THF
9 mL). After 1-2 min HOAc was added to quench the reaction.
The reaction was warmed to room temperature and allowed
to stir for 18 h. The reaction was partitioned between brine
60 mL) and CH
form at this stage), and the organic layer was washed with
saturated NaHCO , forming a creamy white organic phase.
The organic phase was dried (Na SO ) and concentrated to a
yellow-white foam. Purification by column chromatography
EtOAc-petroleum ether) yielded 9 as a white solid (0.400 g,
3%): mp 99-101 °C; R 0.54 (30:70 EtOAc-petroleum ether);
H NMR (500 MHz, CDCl ) δ 0.08 (s, 3H), 0.10 (s, 3H), 0.90
3
3
-
1
700 (s), 1161 (s) cm ; HRMS (CI) m/z calculated for C13
4
21
H -
+
NO Na (M + Na) 278.1368, found 278.1381.
(
2-ter t-Bu t oxyca r b on yla m in o-3,5-d im et h ylh ex-5-en o-
ic Acid (13) a n d 2-ter t-Bu toxy-ca r bon yla m in o-3,5-d i-
m eth ylh ex-4-en oic Acid (2). To a solution of olefin 12 (22
(
2 2
Cl (140 mL) (note: major emulsions may
3 4
mg, 86.2 µmol) and Pd(PPh ) (5 mg, 4.31 µmol) in THF (0.5
3
mL) was added poly(methylhydrosiloxane) (PMHS,15 mg, 224
µmol, 2.6 mequiv) in one portion. After 18 h, the reaction
turned dark yellow and was diluted with dichloromethane and
2
4
(
washed with 10% HCl, saturated NaHCO
organic phase was dried (Na SO ), concentrated, and purified
by column chromatography (hexanes to 50:50 EtOAc-hexanes)
3
, and brine. The
6
f
2
4
1
3
J . Org. Chem, Vol. 69, No. 3, 2004 819

Tarver and J oullie´
to afford a clear oil as 2.6:1 mixture of 13 and 2. Data for 13:
(2 × 20 mL). The organic phase was dried over Na
2 4
SO and
1
R
0
f
0.16 (50:50 EtOAc-hexanes); H NMR (500 MHz, CDCl
.87 (d, J ) 7.0 Hz, 3H), 1.43 (s, 9H), 1.70 (s, 3H), 1.90 (dd,
J ) 13.9,8.1 Hz, 1H), 2.14 (dd, J ) 13.9,6.8 Hz, 1H), 2.25-
.39 (m, 1H), 4.30-4.43 (m, 1H), 4.72 (s, 1H), 4.81 (s, 1H), 4.97
3
) δ
concentrated to afford 14 as a white foam (24 mg, 100%): R
f
1
0. 16 (50:50 EtOAc-hexanes); H NMR (500 MHz, CDCl ) δ
3
0.76 (d, J ) 7.0 Hz, 3H), 1.47 (s, 9H), 1.70 (s, 3H), 1.78-1.91
(m, 1H), 3.67 (m, J ) 4.7,1.1 Hz, 2H), 3.76 (d, J ) 9.0 Hz, 1H),
3.92-4.06 (m, 1H), 4.88 (s, 1H), 4.89 (s, 1H), 5.05 (d, J ) 7.7
2
1
3
(
2
3
d, J ) 9.9 Hz, 1H); C NMR (125 MHz, CDCl
3
) δ 14.4, 22.1,
8.3, 33.3, 41.8, 57.5, 80.5, 112.8, 124.4, 142.8, 174.2; IR (neat)
337 (br), 2968 (m), 2917 (s), 2848 (w), 1714 (s), 1392 (m), 1367
Hz, 1H); 13C NMR (125 MHz, CDCl
37.9, 53.4, 64.4, 78.4, 80.3, 113.6, 145.4, 157.3; IR (neat) 3342
) δ 12.3, 16.7, 28.4, 29.7,
3
-
1
(m), 1253 (m), 1163 (s), 1074 (m) cm ; HRMS m/z calculated
(br), 2971 (s), 2925 (s), 2247 (w), 1682 (s), 1516 (s), 1455 (m),
+
-1
for C13
: R 0.16 (50:50 EtOAc-hexanes); H NMR (500 MHz, CDCl
δ 1.02 (d, J ) 6.9 Hz, 3H), 1.45 (s, 9H), 1.62 (s, 3H), 1.69 (s,
H), 2.82-2.96 (m, 1H), 4.09-4.25 (m, 1H), 4.96 (d, J ) 9.6
H
24NO
4
(M + H) 258.1705, found 258.1696. Data for
1366 (s), 1253 (s), 1173 (s), 1026 (m), 900 (m), 735 (w) cm ;
1
+
2
f
3
)
4
HRMS m/z calculated for C13H25NO Na (M + Na) 282.1681,
found 282.1675.
3
1
3
Hz, 1H), 5.03 (m, 1H); C NMR (125 MHz, CDCl
3
) δ 18.0, 25.9,
8.3, 29.7, 35.2, 41.8, 80.5, 112.8, 124.5, 142.8, 174.2; IR (neat)
345 (br), 2973 (m), 2920 (m), 2360 (s), 2340 (s), 1680 (s), 1391
Ack n ow led gm en t. This work was supported by
2
3
.
UNCF Merck Science Initiative.
-1
(m), 1366 (m), 1252 (m), 1168 (s), 1074 (m), 668 (s) cm ; HRMS
+
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
m/z calculated for C13
58.1696.
3-H yd r oxy-1-h yd r oxym et h yl-2,4-d im et h ylp en t -4-en -
H
24NO
4
(M + H) 258.1705, found
1
13
cedures for 3, E-4, and E/Z-4; H NMR and C NMR spectra
of all new compounds; and tables of X-ray structural data in
CIF format and ORTEP diagrams for 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
2
(
yl)ca r ba m ic Acid ter t-Bu t yl E st er (14). To a solution of
lactone 12 (24 mg, 94 µmol) in THF (1.5 mL) was added sodium
borohydride (7 mg, 0.188 mmol) in one portion. After 24 h,
the reaction was diluted with water and extracted with EtOAc
J O035401M
8
20 J . Org. Chem., Vol. 69, No. 3, 2004