Convergent synthesis of (2R,3R,8R,9R)-N-Boc-ADDA

Article abstract of DOI:10.1021/jo800574g

(Figure Presented) The convergent synthesis of N-Boc-(2R,3R,8R,9R,4E,6E)-3- amino-9-methoxy-2,6,8-trimethyl-10-phenyldecadenoic acid (enantio-N-Boc-ADDA) is reported. Our flexible approach takes advantage of highly efficient non-aldol aldol and cross-metathesis methodologies.

Full text of DOI:10.1021/jo800574g

Convergent Synthesis of (2R,3R,8R,9R)-N-Boc-ADDA
Sebastien Meiries and Rodolfo Marquez*,†
WestCHEM, UniVersity of Glasgow, Joseph Black Building, UniVersity AVenue, Glasgow G12 8QQ, U.K.
r.marquez@chem.gla.ac.uk
ReceiVed March 14, 2008
The convergent synthesis of N-Boc-(2R,3R,8R,9R,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phe-
nyldecadenoic acid (enantio-N-Boc-ADDA) is reported. Our flexible approach takes advantage of highly
efficient non-aldol aldol and cross-metathesis methodologies.
Introduction
Protein phosphatases (PPs) are a crucial group of proteins
involved in a variety of processes including cell division,
neurotransmission, memory, and learning. Some of the most
important PPs are the serine-threonine phosphatases 1, 2A/B,
and 4 (PP1, PP2A/B, and PP4), which have been shown to have
significant roles in signal transduction pathways.1 Unfortunately,
despite extensive testing, our understanding of the relative
pharmacological functions of the various phosphatases remains
fairly limited due to their structural similarity and the lack of
selective inhibitors.2
Motuporin 1, nodularin 2, and the microcystins (i.e., micro-
cystin LA, 3) (Figure 1) are macrocyclic peptides of marine
origin (the microcystins and nodularin were isolated from
cyanobacteria while motuporin was isolated from the marine
sponge Theonella swinhoei).3,4 Although all of them exhibit
biological activity as protein phosphatase inhibitors, their toxicity
has kept them from being developed as potential therapeutic
leads.5
Structurally, the microcystins nodularin and motuporin share
the unusual ꢀ-amino acid unit (2S,3S,8S,9S,4E,6E)-3-amino-9-
† Ian Sword Lecturer of Organic Chemistry.
(1) Launey, T.; Endo, S.; Sakai, R.; Harano, J.; Ito, M. Proc. Nat. Acad.
U.S.A. 2004, 101, 676.
FIGURE 1. Motuporin 1, nodularin 2, and microcystin LA3.
methoxy-2,6,8-trimethyl-10-phenyldecadenoic acid 4 (“ADDA”)
which upon truncation causes the PP inhibitory activity of the
macrocyclic peptides to cease. The unique structure of ADDA
as well as its biological relevance has inspired a number of
synthetic approaches developed to date.6
Reports by Chamberlin and co-workers have demonstrated
that microcystin analogues 5 incorporating the N-acylated
ADDA chain and a single amino acid retain moderate activity
(2) (a) McCluskey, A.; Sakoff, J. A. Mini ReV. Med. Chem. 2001, 1, 43. (b)
McCluskey, A.; Sim, A. T. R.; Sakoff, J. A. J. Med. Chem. 2002, 45, 1151.
(3) (a) Rinehart, K. L.; Harada, K.; Namikoshi, M.; Chen, C.; Harvis, C. A.;
Munro, M. H. G.; Blunt, J. W.; Mulligan, P. E.; Beasley, V. R.; Dahlem, A. M.;
Carmichael, W. W. J. Am. Chem. Soc. 1988, 110, 8557. (b) Dilip de Silva, E.;
Williams, D. E.; Andersen, R. J.; Klix, H.; Holmes, C. F. B.; Allen, T. M.
Tetrahedron Lett. 1992, 33, 1561.
(4) (a) Aggen, J. B.; Humphrey, J. M.; Gauss, C. M.; Huang, H. B.; Nairn,
A. C.; Chamberlin, A. R. Bioorg. Med. Chem. 1999, 7, 543. (b) Sheppeck, J. E.,
II; Gauss, C. M.; Chamberlin, A. R. Bioorg. Med. Chem. 1997, 5, 1739.
10.1021/jo800574g CCC: $40.75
Published on Web 06/11/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5015–5021 5015

Meiries and Marquez
SCHEME 1. Retrosynthetic Analysis
FIGURE 2. ADDA 4 and ADDA analogue 5.
as PP1/PP2A inhibitors (Figure 2).7,8 Interestingly, naturally
occurring 6Z-ADDA3 nodularin and microcystin analogues dis-
play none of the toxicity associated with the parent compounds.9
Iso-Motuporin 6 was recently isolated from the marine sponge
T. swinhoei, showcasing a structurally novel iso-ADDA frag-
ment (Figure 3).10 This discovery, together with the previously
reported biological activity of the 6Z-ADDA3 derivates raise
the possibility that stereoisomeric forms of the ADDA scaffold
(and conversely microcystin, motuporin, and nodularin) provide
an alternative starting point for the development of novel
biological chemical probes to study and dissect phosphatase
activity.
stereochemistry on its biological activity both on its own and
when attached to other naturally occurring macrocyclic peptides.
Retrosynthetically, we envisioned enantio-N-Boc-ADDA 7
as having originated through the convergent cross-metathesis
coupling of diene 8 with vinyl lactam 9. Diene 8 could be readily
secured through the olefination of aldehyde 10, in turn easily
accessible through Jung’s non-aldol aldol methodology.11 The
ꢀ-lactam coupling partner on the other hand, could be accessed
through the condensation of vinyl enol ether 11 and a suitably
protected isocyanate 12 (Scheme 1).
Our synthesis began with phenylacetaldehyde 13 which was
olefinated and reduced to afford the desired allylic alcohol 14
in excellent yield and with complete E selectivity. A Sharpless
reagent-controlled epoxidation of alkenol 14 then generated the
desired epoxide 15 in high yield and good enantiomeric excess
(Scheme 2).
FIGURE 3. Iso-Motuporin 6 bearing the previously unidentified iso-
ADDA chain.
SCHEME 2. Non-aldol Aldol Approach to Diene Unit
As part of our efforts toward the generation of novel ADDA
isoforms, we would like to report the first convergent synthesis
of enantio-N-Boc-ADDA which takes advantage of a key E,E-
selective diene cross-metathesis coupling to introduce the core
diene unit. An efficient synthesis of enantio-ADDA would not
only provide a proof of concept for our synthetic approach but
also allow us to determine the effect of ADDA’s absolute
(5) Blom, J. F.; Juttner, F. Toxicon 2005, 46, 465.
(6) (a) Cundy, D. J.; Donohue, A. C.; McCarthy, T. D. J. Chem. Soc., Perkin
Trans. 1 1999, 559. (b) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4914. (c)
Kim, H. Y.; Toogood, P. L. Tetrahedron Lett. 1996, 37, 2349. (d) D’Aniello,
F.; Mann, A.; Taddei, M. J. Org. Chem. 1996, 61, 4870. (e) Sin, N.; Kallmerten,
J. Tetrahedron Lett. 1996, 37, 5645. (f) Humphrey, J. M.; Aggen, J. B.;
Chamberlin, A. R. J. Am. Chem. Soc. 1996, 118, 11759. (g) Valentekovich, R. J.;
Schreiber, S. L. J. Am. Chem. Soc. 1995, 117, 9069. (h) Beatty, M. F.; Jennings-
White, C.; Avery, M. A. J. Chem. Soc., Perkin Trans. 1 1992, 1637. (i)
Chakraborty, T. K.; Joshi, S. P Tetrahedron Lett. 1990, 31, 2043. (j) Namikoshi,
M.; Rinehart, K. L.; Dahlem, A. M.; Beasley, V. R.; Carmichael, W. W.
Tetrahedron Lett. 1989, 30, 4349. (k) Pearson, C.; Rinehart, K. L.; Sugano, M.;
Costerison, J. R. Org. Lett. 2000, 2, 2901. (l) Hu, T.; Panek, J. S. J. Org. Chem.
1999, 64, 3000. (m) Bauer, S. M.; Armstrong, R. W. J. Am. Chem. Soc. 1999,
121, 6355.
(7) Gulledge, B. M.; Aggen, J. B.; Eng, H.; Sweimeh, K.; Chamberlin, A. R.
Bioorg. Med. Chem. Lett. 2003, 13, 2907.
(8) Gulledge, B. M.; Aggen, J. B.; Huang, H. B.; Nairn, A. C.; Chamberlin,
A. R Curr. Med. Chem. 2002, 9, 1991.
(9) Rinehart, K. L.; Namikoshi, M.; Choi, B. Y. J. App. Phycol. 1994, 6,
159.
Protection of alcohol 15 proceeded in near-quantitative yield
to afford the TBS silyl ether 16, which under Jung’s non-aldol
(10) Wegerski, C. J.; Hammond, J.; Tenney, K.; Matainaho, T.; Crews, P. J.
Nat. Prod. 2007, 70, 89.
5016 J. Org. Chem. Vol. 73, No. 13, 2008

ConVergent Synthesis of (2R,3R,8R,9R)-N-Boc-ADDA
SCHEME 4. Diene-Alkene Cross-Methatesis
aldol conditions generated propionate 17 in high yield and as a
single diastereomer. Olefination of aldehyde 17 with phosphine
oxide 1812 afforded the desired diene 19 as mixture of isomers
in which the major component exhibited the required internal
E double-bond geometry. The double-bond geometry was
1
corroborated through H NMR and NOE analysis.
Efficient desilylation of diene 19E followed by methylation
of the resulting free hydroxyl group completed the synthesis of
the enantio-ADDA unit’s left-hand side 20 (Scheme 2).
The synthesis of the desired ꢀ-lactam coupling partner began
with the careful treatment of vinyl acetate with chlorosulfonyl
isocyanate 21 to generate the crude acetoxyazetidinone 23 in
moderate yield (Scheme 3).13 Acetoxyazetidinone 23 was then
converted to sulfone 24 which upon treatment with vinylmag-
nesium bromide afforded the vinyl azetidinone 25 in good
overall yield.14
Protection of vinyl azetidinone 25 proceeded in near-quan-
titative yield to generate the N-TBS silyl amide 26. Enolization
and methylation of lactam 26 completed the synthesis of the
required ꢀ-lactam core unit 27 in good yield and as a single
diastereomer. The relative configuration was corroborated through
1H NMR and NOE analysis.
greatly improved through the use of the Boc-protected lactam
29. To the best of our knowledge, this is the first example of a
diene-alkene cross-metathesis reaction involving two electron-
rich species.16
Separation of the diastereomeric mixture through the use of
semi-preparative HPLC under reversed-phase conditions allowed
the isolation of compound 31 with near-quantitative efficiency.
The undetected compound 32 appears to have decomposed under
the HPLC separation conditions.
Introduction of the Boc protecting group proceeded in
quantitative yield to afford the required carbamate unit 29
(Scheme 3).
Finally, a near-quantitative base-promoted ring opening of
lactam 31 then completed our efficient and convergent synthesis
of enantio-N-Boc-ADDA 7 (Scheme 5). The spectral data of
enantio-N-Boc-ADDA matched that reported for N-Boc-ADDA.
As expected, enantio-N-Boc-ADDA had almost the exact
opposite optical rotation [R]23D +15.1 (c ) 1.0, CHCl3) to that
SCHEME 3. Synthesis of ꢀ-Lactam Coupling Partner
reported for N-Boc-ADDA [R]23 -15.7 (c ) 1.0, CHCl3).6d
D
SCHEME 5. Completion of the Synthesis of enantio-N-Boc
ADDA
In conclusion, we have completed the efficient and convergent
synthesis of (2R,3R,8R,9R)-N-Boc-ADDA taking advantage of
non-aldol aldol and cross-metathesis methodologies to introduce
the key functionality.
Our efficient approach can be easily scaled up and compares
favorably with the other approaches reported for the synthesis
of ADDA in terms of convergence and flexibility despite the
generation of the mixture of diastereomers during the cross-
metathesis step (10 steps starting from phenyl acetaldehyde 13
and 10% overall yield). Furthermore, in most steps, the inter-
mediate compounds can be taken on crude to subsequent steps
in similar or better yields.
Having successfully achieved the synthesis of both the left
and right-hand side units, the crucial cross-metathesis couplings
were attempted.15 After extensive catalyst screening under a
wide range of experimental conditions, the desired cross-meta-
thesis was successfully achieved between diene 20 and ꢀ-lactams
27-29 to generate the desired product as a single E,E-diene
and a 1:1 mixture of diastereomers. The cross-metathesis was
only successful in the presence of the second generation
Hoveyda-Grubbs catalyst 30 (Scheme 4), and the yield was
(11) (a) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115, 12208.
(b) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1997, 119, 12150. (c) Jung,
M. E.; Lee, W. S.; Sun, D. Org. Lett. 1999, 1, 307. (d) Jung, M. E.; Marquez,
R. Org. Lett. 2000, 2, 1669.
We are currently in the process of evaluating enantio-N-Boc
ADDA’s full biological profile, while simultaneously developing
new potential phosphatase inhibitors using this synthetic approach.
(12) Kondo, H.; Oritani, T.; Kiyota, H. Eur. J. Org. Chem. 2000, 3459.
(13) Firestone, R. A.; Barker, P. L.; Pisano, J. M.; Ashe, B. M.; Dahlgren,
M. E. Tetrahedron 1990, 46, 2255.
(14) Cheung, K. M.; Shoolingin-Jordan, P. M. Tetrahedron 1997, 53, 15807.
(15) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(16) (a) Dewi, P.; Randl, S.; Blechert, S. Tetrahedron Lett. 2005, 46, 577.
(b) Moura-Letts, G.; Curran, D. P. Org. Lett. 2007, 9, 5.
J. Org. Chem. Vol. 73, No. 13, 2008 5017

Meiries and Marquez
(1H, bs), 2.90 (1H, dd, J ) 14.7, 6.2 Hz), 3.00 (1H, dd, J ) 14.7,
6.4 Hz), 3.33 (1H, t, J ) 6.3 Hz), 3.61 (1H, d, J ) 12.3 Hz), 3.73
(1H, d, J ) 12.3 Hz), 7.26-7.38 (5H, m); 13C NMR (100 MHz,
CDCl3) δ 14.5, 34.7, 60.3, 61.4, 65.3, 126.7, 128.7, 128.8, 137.6;
[R]25D +23.2 (c ) 1.0, CHCl3); IR (thin film) νmax ) 3419, 3029,
2965, 2926, 2870, 1496, 1454, 1038, 742, 700 cm-1; HRMS (EI)
obsd M+ 178.0995, calcd for C11H14O2 178.0994.
Experimental Section
(E)-2-Methyl-4-phenylbut-2-en-1-ol, 14. To a stirred solution
of commercially available phenylacetaldehyde 13 (6.05 g, 504
mmol) in dry benzene (120 mL) was added (1-ethoxycarbonyleth-
ylidene)triphenylphosphorane (23.93 g, 660 mmol), and the resultant
solution was refluxed overnight. The reaction mixture was con-
centrated under reduced pressure, and the resultant yellow residue
was washed with petroleum ether (5 × 150 mL) to crush out
triphenylphosphine oxide. After filtrations, the combined washings
were concentrated under vacuum to give a crude residue (9.34 g)
which was purified by column chromatography (silica gel, 1-2%
diethyl ether in 40-60 petroleum ether) to afford (E)-ethyl 2-me-
thyl-4-phenylbut-2-enoate (8.64 g, 84%) as a clear and colorless
(((2R,3R)-3-Benzyl-2-methyloxiran-2-yl)methoxy)(tert-bu-
tyl)dimethylsilane, 16. A solution of epoxide 15 (207 mg, 1.16
mmol) in anhydrous N,N-dimethylformamide (6 mL) was treated
with imidazole (237 mg, 3.48 mmol) and stirred until homogeneous.
The reaction mixture was treated with TBSCl (277 mg, 1.84 mmol)
and stirred under argon until completion as indicated by TLC
analysis (2 h). The reaction was quenched by the addition of a 1:1
mixture of diethyl ether/water (14 mL total volume). The mixture
was then slightly acidified by addition of aq HCl (1.0 M, 1.5 mL)
before the two phases were separated. The organic extracts were
washed with water (10 mL) and brine (10 mL). The combined ether
extracts were dried over anhydrous sodium sulfate and concentrated
under vacuum to yield a dark yellow crude oil (331 mg). Flash
column chromatography (silica gel, 30% ethyl acetate in hexane)
gave the desired silyl protected epoxide 16 (325 mg, 95%) as a
1
viscous oil: H NMR (400 MHz, CDCl3) δ 1.32 (3H, t, J ) 7.1
Hz), 2.00 (3H, appq, J ) 1.4 Hz), 3.57 (2H, d, J ) 7.6 Hz), 4.23
(2H, q, J ) 7.1 Hz), 6.96 (1H, tq, J ) 7.6, 1.4 Hz), 7.22-7.37
(5H, m); 13C NMR (100 MHz, CDCl3) δ 12.6, 14.3, 34.9, 60.6,
126.4, 128.5, 128.6, 128.7, 139.1, 140.0, 168.1; IR (thin film) νmax
) 3029, 2981, 2932, 1710, 1255, 742, 699 cm-1; HRMS (EI) obsd
M+ 204.1152, calcd for C13H16O2 204.1150.
To a stirred solution of (E)-ethyl 2-methyl-4-phenylbut-2-enoate
(2.11 g, 103 mmol) in anhydrous diethyl ether (40 mL) was added
LiAlH4 dropwise (1.0 M in hexanes, 10.0 mL, 10.0 mmol) at 0 °C.
The reaction was allowed to warm to room temperature until
completion as indicated by TLC (4 h). The reaction mixture was
quenched at 0 °C by addition of water (2 mL) and aq sodium
hydroxide (20%, 1 mL). The workup was continued by the further
addition of water (40 mL) and aq sodium hydroxide (20%, 20 mL).
The mixture was stirred for 30 min, after which the mineral solid
precipitate was filtrated and washed with diethyl ether (120 mL).
The organic extracts were dried over anhydrous sodium sulfate and
concentrated under vacuum to give a crude residue (1.71 g). Flash
column chromatography (silica gel, 60% diethyl ether in 40-60
petroleum ether) provided the desired alcohol 14 (1.51 g, 90%) as
1
clear and colorless viscous oil: H NMR (400 MHz, CDCl3) δ
-0.03 (3H, s), 0.00 (3H, s), 0.84 (9H, s), δ 1.36 (3H, s), 2.78 (1H,
dd, J ) 14.8, 6.7 Hz), 2.93 (1H, dd, J ) 14.8, 6.0 Hz), 3.09 (1H,
appt, J ) 6.3 Hz,), 3.52 (1H, d, J ) 11.1 Hz), 3.57 (1H, d, J )
11.1 Hz), 7.18-7.28 (5H, m); 13C NMR (100 MHz, CDCl3) δ -5.4,
14.4, 18.3, 25.9, 34.7, 61.2, 61.3, 68.0, 126.5, 128.6, 128.7, 137.8;
[R]25 -2.5 (c ) 1.0, CHCl3); IR (thin film) νmax ) 2929, 2857,
D
1689, 1471, 1461, 1255, 1096, 837 cm-1; HRMS (CI) obsd (M +
H)+ 293.1935, calcd for C17H29O2Si 293.1937.
(2S,3R)-3-(tert-Butyldimethylsilyloxy)-2-methyl-4-phenylbu-
tanal, 17. A -78 °C solution of the epoxy alcohol 16 (1.35 g,
4.60 mmol) in anhydrous dichloromethane (125 mL) was sequen-
tially treated with anhydrous DIPEA (2.42 mL, 1.80 g, 13.89 mmol)
and TBSOTf (3.19 mL, 3.67 g, 13.89 mmol). The mixture was
then slowly allowed to warm to -45 °C and stirred until completion
as indicated by TLC analysis (3 h). The cold mixture was then
cooled once again to -78 °C before being poured into a separating
funnel containing a 1:1 mixture of diethyl ether and 1 M aq NaHPO4
(100 mL total volume). The phases were separated, and the organic
layer was then successively washed with water (2 × 50 mL) and
aq NaHPO4 (1.0 M, 50 mL). The combined aqueous fractions were
extracted with diethyl ether (20 mL), and the organic extracts were
combined and dried over anhydrous sodium sulfate. The solvents
were evaporated under reduced pressure to provide a light yellow
crude oil (3.25 g) which was purified by flash chromatography
(silica gel, 1% TEA, 20% dichloromethane in 40-60 petroleum
ether) to afford the pure aldehyde 17 as a clear and colorless viscous
oil (948 mg, 70%). The aldehyde proved unstable upon standing,
and it could not be stored for any periods of time without
decomposition being observed: 1H NMR (400 MHz, CDCl3) δ
-0.14 (3H, s), 0.00 (3H, s), 0.85 (9H, s), 1.15 (3H, d, J ) 7.0 Hz),
2.35 (1H, qd, J ) 6.9, 3.0 Hz), 2.80 (2H, d, J ) 7.0 Hz), 4.39 (1H,
td, J ) 7.0, 3.0 Hz), 7.16-7.32 (5H, m), 9.70 (1H, bs); 13C NMR
(100 MHz, CDCl3) δ -4.9, -4.7, 7.3, 18.0, 25.7, 41.2, 50.5, 73.2,
126.6, 128.5, 129.4, 138.0, 204.9; [R]25D +37.0 (c ) 1.0, CHCl3);
IR (thin film) νmax ) 3028, 2954, 2929, 2710, 1727, 1254, 1104,
1032, 837, 777, 700 cm-1; HRMS (CI) obsd (M + H)+ 293.1938,
calcd for C17H29O2Si 293.1937.
1
a clear and colorless viscous oil: H NMR (400 MHz, CDCl3) δ
1.80 (3H, s), 1.98 (1H, bs), 3.42 (2H, d, J ) 7.4 Hz), 4.04 (2H, s),
5.64 (1H, tq, J ) 7.4, 1.4 Hz), 7.23-7.33 (5H, m); 13C NMR (100
MHz, CDCl3) δ 13.8, 33.9, 68.6, 124.6, 126.0, 128.4, 128.6, 135.7,
141.0; IR (thin film) νmax ) 3324, 3027, 2915, 2860, 1493, 1453,
1016, 741, 698 cm-1; HRMS (EI) obsd M+ 162.1043, calcd for
C11H14O 162.1045.
((2R,3R)-3-Benzyl-2-methyloxiran-2-yl)methanol, 15. To flame-
dried 4 Å molecular sieves (32 g in powder) in a round-bottom
flask was added dry dichloromethane (250 mL) followed by freshly
distilled D-(-)-DIPT (13.55 mL, 14.95 g, 63.80 mmol). After the
mixture was cooled to -30 °C, freshly distilled Ti(OiPr)4 (17.82
mL, 17.11 g, 60.19 mmol) was added, and the reaction was allowed
to stir at -30 °C for 30 min. After the addition of t-BuOOH (5.5
M in decanes, 64.0 mL, 352 mmol) at -25 °C, the solution was
allowed to stir for a further 1 h at -30 °C before being treated
with a solution of alcohol 14 (27.70 g, 171 mmol) in anhydrous
dichloromethane (250 mL). The reaction was stirred for 1 h at -30
°C and then allowed to warm slowly to room temperature overnight.
The reaction was quenched by addition of water (800 mL) followed
by an aq sodium hydroxide solution (30%) saturated with NaCl
(175 mL total volume). The resultant milky mixture was filtrated
through cotton wool and sand (2 kg) and then washed with diethyl
ether (1000 mL) and dichloromethane (1000 mL). The phases were
separated, and the aqueous layer was washed with dichloromethane
(250 mL). The organic extracts were combined, dried over anhy-
drous sodium sulfate, and concentrated under vacuum to afford a
viscous oil (51.28 g). Purification of the resulting crude residue by
flash column chromatography (silica gel, 30% ethyl acetate in
40-60 petroleum ether) afforded the pure desired epoxide 15 (28.7
g, 95%, ee ) 90%) as a clear and colorless viscous oil. The
enantiomeric excess was determined through HPLC analysis with
a chiral column using hexanes/2-propanol (99:1) at a flow rate of
tert-Butyl ((2R,3R,4E)-3,5-Dimethyl-1-phenylhepta-4,6-dien-
2-yloxy)dimethylsilane, 19E, and tert-Butyl ((2R,3R,4Z)-3,5-
Dimethyl-1-phenylhepta-4,6-dien-2-yloxy)dimethylsilane, 19Z. A
-78 °C solution of phosphine oxide 18 (1.20 g, 4.68 mmol) in
anhydrous THF (16 mL) was treated with the dropwise addition of
n-butyllithium (2.5 M in hexanes, 1.80 mL, 4.50 mmol). The
reaction was stirred for 20 min at -78 °C before a solution of
freshly distilled HMPA (1.65 mL, 1.70 g, 9.48 mmol) in dry THF
(5 mL) was incorporated. A solution of aldehyde 17 (913 mg, 3.11
1
0.75 mL/min: H NMR (400 MHz, CDCl3) δ 1.45 (3H, s), 2.06
5018 J. Org. Chem. Vol. 73, No. 13, 2008

ConVergent Synthesis of (2R,3R,8R,9R)-N-Boc-ADDA
mmol) in anhydrous THF (5 mL) was then added dropwise, and
the reaction mixture was stirred at -78 °C until completion as
indicated by TLC analysis (15 min). The reaction was quenched
with water (20 mL), and the two phases were separated. The organic
layer was sequentially washed with water (2 × 20 mL) and satd
aq LiBr (2 × 20 mL) and dried over anhydrous sodium sulfate.
The solvent was evaporated in vacuo to give a viscous yellow oil
(1.69 g) which was then purified by flash chromatography (silica
gel, 1% TEA in 40-60 petroleum ether) to afford 565 mg of the
pure TBS-protected diene 19E and 188 mg of the minor diene 19Z
as colorless, clear, and viscous oils (753 mg, 73% overall yield).
4-Acetoxyazetidinone, 23. Freshly distilled vinyl acetate (286
mL, 267.1 g, 3.10 mol) was treated with chlorosulfonyl isocyanate
(50 mL, 81.3 g, 574 mmol) at 0 °C. The reaction was followed by
1H NMR, and the maximum conversion was obtained after 1 h,
when the reaction mixture started to turn yellow. The reaction was
then cooled to -78 °C and cannulated into a 2 L conical flask
containing a previously made mixture of sodium bicarbonate (130
g, 1.54 mol), sodium sulfite (90 g, 714 mmol), ice (250 g, 13.88
mol), and water (250 g, 13.88 mol) under stirring and open to the
air. It was imperative that the temperature of the conical flask was
not allowed to warm up above 0 °C throughout the transfer. The
mixture was then stirred until the bubbling ceased (1 h) and was
then poured into a separating funnel. The phases were separated,
and the organic layer was extracted with water (5 × 150 mL). The
combined aqueous extracts were then extracted with dichlo-
romethane (3 × 150 mL) followed by saturation of the aqueous
phase with sodium chloride. The saturated aqueous solution was
then extracted with dichloromethane (2 × 150 mL) and ethyl acetate
(150 mL). The combined organic layers were dried over anhydrous
sodium sulfate and concentrated at 30 °C under reduced pressure
to give the desired azetidinone 23 as viscous light yellow oil which
was pure by 1H NMR analysis and was used in the next step without
any further purification (17.8 g, 24%): 1H NMR (400 MHz, CDCl3)
δ 2.05 (3H, s), 2.94 (1H, ddd, J ) 15.2, 1.4, 0.5 Hz), 3.20 (1H,
ddd, J ) 15.2, 4.1, 2.6 Hz), 5.76 (1H, dd, J ) 4.1, 1.4 Hz), 6.82
(1H, s).
1
19E: H NMR (400 MHz, CDCl3) δ -0.26 (3H, s), 0.02 (3H,
s), 0.87 (9H, s), 1.00 (3H, d, J ) 6.8 Hz), 1.56 (3H, d, J ) 1.2
Hz), 2.45-2.54 (1H, m), 2.69 (1H, dd, J ) 13.6, 6.4 Hz), 2.82
(1H, dd, J ) 13.6, 6.0 Hz), 3.78 (1H, appq, J ) 6.2 Hz), 4.93 (1H,
d, J ) 10.8 Hz), 5.07 (1H, d, J ) 17.4 Hz), 5.42 (1H, d, J ) 9.7
Hz), 6.34 (1H, ddd, J ) 17.4, 10.7, 0.4 Hz), 7.15-7.28 (5H, m);
13C NMR (100 MHz, CDCl3) δ -4.8, -4.5, 11.8, 15.2, 18.1, 25.9,
37.1, 41.7, 77.3, 110.7, 126.0, 128.1, 129.7, 132.9, 136.9, 139.1,
141.8; [R]20D +23.0 (c ) 1.0, CHCl3); IR (thin film) νmax ) 3027,
2956, 2928, 2856, 1254, 1100, 1085, 835, 774, 699 cm-1
.
1
19Z: H NMR (400 MHz, CDCl3) δ -0.15 (3H, s), 0.00 (3H,
s), 0.87 (9H, s), 0.98 (3H, d, J ) 6.8 Hz), 1.68 (3H, s), 2.51-2.56
(1H, m), 2.65 (2H, dd, J ) 8.4, 1.3 Hz), 3.76-3.80 (1H, m), 4.96
(1H, d, J ) 10.7 Hz), 5.11 (1H, d, J ) 17.4 Hz), 5.58 (1H, d, J )
9.6 Hz), 6.44 (1H, dd, J ) 17.4, 10.7 Hz), 7.06-7.28 (5H, m); 13
C
4-(Phenylsulfonyl)azetidin-2-one, 24. Acetoxyazetidinone 23
(27.14 g, 210 mmol) was dissolved in water (110 mL) and treated
with sodium phenyl sulfinate (35.0 g, 213.2 mmol). The mixture
was refluxed for 20 min, and the yellow reaction mixture was
then cooled to room temperature. The reaction was then extracted
with dichloromethane (5 × 150 mL), the combined extracts were
dried over anhydrous sodium sulfate and the solvent was
removed under reduced pressure to give the pure sulfone 24 as
a white powder (36.56 g, 173 mmol, 82%). The sulfone 24 was
NMR (100 MHz, CDCl3) δ -4.8, -4.6, 12.1, 16.9, 18.1, 25.9,
37.2, 41.3, 77.4, 110.7, 126.0, 128.2, 129.7, 133.9, 134.8, 139.4,
142.0; [R]25D -11.8 (c ) 1.0, CHCl3). IR (thin film) νmax ) 3027,
2956, 2928, 2856, 1254, 1100, 1085, 835, 774, 699 cm-1
.
((2R,3R,4E)-2-Methoxy-3,5-dimethylhepta-4,6-dienyl)ben-
zene, 20. A solution of TBS-protected diene 19E (544 mg, 1.65
mmol) in anhydrous THF (30 mL) was transferred into a round-
bottom flask containing flame-activated powdered 4 Å molecular
sieves (2 g). The suspension was treated with tetrabutylammonium
fluoride (1.0 M in THF, 4.90 mL, 4.90 mmol), and the resulting
mixture was stirred at room temperature until completion as
indicated by TLC analysis (15 min). The mixture was then quenched
with water (40 mL) and the reaction extracted with ethyl acetate
(2 × 20 mL). The organic extracts were combined and dried over
anhydrous sodium sulfate, and the solvents were removed under
vacuum. The resulting brown oil (447 mg) was then taken on crude
to the next reaction without any further purification.
1
used in the next reaction without any further purification: H
NMR (400 MHz, CDCl3) δ 3.22 (1H, dd, J ) 15.5, 2.3 Hz),
3.31 (1H, dd, J ) 15.5, 5.0 Hz), 4.73 (1H, dd, J ) 5.0, 2.3 Hz),
6.47 (1H, bs), 7.62-7.66 (2H, m), 7.73-7.78 (1H, m) 7.93-7.96
(2H, m); 13C NMR (100 MHz, CDCl3) δ 41.6, 64.8, 129.3, 129.7,
134.6, 135.0, 164.4; IR (thin film) νmax ) 3490, 3253, 3017,
2923, 2852, 1769, 1313, 1148 cm-1; HRMS (CI) obsd (M +
H)+ 212.0374, calcd for C9H10O3NS 212.0381.
4-Vinylazetidin-2-one, 25. A -78 °C solution of sulfone 24
(36.56 g, 172 mmol) in anhydrous THF (620 mL) was treated with
vinylmagnesium bromide (1.0 M in THF, 426 mL, 426 mmol),
and the reaction was vigorously stirred at -78 °C for 30 min.
The mixture was then consequently allowed to warm to 0 °C
and stirred for 50 min. The reaction was then warmed to room
temperature and stirred for 2 h. The reaction was quenched with
satd aq ammonium chloride (185 mL) and stirred for a further
15 min. The crude mixture was then filtered through cotton wool,
the two resulting phases were separated, and the aqueous layer
was extracted with dichloromethane (3 × 500 mL). The
combined organic extracts were collected and dried over anhyd-
rous sodium sulfate and the solvents evaporated under vacuum
to give the crude product as an orange/brown oil. The crude
product was purified by flash chromatography (silica gel, 50%
ethyl acetate in 40-60 petroleum ether) to give the pure
vinylazetidinone 25 as a colorless and slightly viscous oil (14.98
g, 90%): 1H NMR (400 MHz, CDCl3) δ 2.67 (1H, dq, J ) 14.8,
1.3 Hz), 3.17 (1H, ddd, J ) 14.8, 5.2, 2.0 Hz), 4.07-4.11 (1H,
m), 5.14 (1H, dt, J ) 10.2, 0.9 Hz), 5.28 (1H, dt, J ) 17.0, 1.0
Hz), 5.88 (1H, ddd, J ) 17.0, 10.2, 7.0 Hz), 6.68 (1H, s); 13C
NMR (100 MHz, CDCl3) δ 44.9, 49.4, 116.9, 137.5, 168.1; IR
(thin film) νmax ) 3471, 3263, 2986, 2924, 1761 cm-1; LRMS
(CI) (M + H)+ 98.18 (100).
Neat KH (1.20 g, 30 mmol) was mixed with anhydrous THF
(90 mL), and the resulting suspension was treated with the crude
dienol at 0 °C. The reaction mixture was then stirred under argon
at 0 °C for 20 min, and iodomethane (1.60 mL, 3.65 g, 25.70 mmol)
was incorporated through a small pad of basic alumina. The reaction
mixture was then allowed to slowly warm to room temperature.
The reaction was stirred at room temperature until completion (2-3
h) and carefully quenched by the slow addition of a satd aq NaHCO3
(70 mL). The phases were separated, and the aqueous layer was
extracted with diethyl ether (30 mL). The organic extract was dried
over anhydrous magnesium sulfate, and the solvent was removed
under reduced pressure. The crude yellow oil (433 mg) obtained
was then purified by flash chromatography (silica gel, 70% toluene
in 40-60 petroleum ether) to afford diene 20 as a colorless and
1
clear viscous oil (347 mg, 92% over two steps): H NMR (400
MHz, CDCl3) δ 1.05 (3H, d, J ) 6.7 Hz), 1.65 (3H, d, J ) 1.2
Hz), 2.57-2.66 (1H, m), 2.70 (1H, dd, J ) 13.9, 7.4 Hz), 2.83
(1H, dd, J ) 13.9, 4.5 Hz), 3.19-3.23 (1H, m), 3.24 (3H, s), 4.97
(1H, d, J ) 10.7 Hz), 5.11 (2H, dd, J ) 17.4, 0.3 Hz), 5.41 (1H,
d, J ) 9.8 Hz), 6.38 (1H, ddd, J ) 17.4, 10.6, 0.6 Hz), 7.17-7.30
(5H, m); 13C NMR (100 MHz, CDCl3) δ 11.9, 16.2, 36.6, 38.2,
58.6, 86.9, 111.1, 125.9, 128.1, 129.4, 133.7, 135.8, 139.4, 141.6;
[R]25 -2.6 (c ) 1.0, CHCl3); IR (thin film) νmax ) 3027, 2955,
D
2928, 2871, 1454, 1096, 700 cm-1; HRMS (CI) obsd (M + H)+
1-(tert-Butyldimethylsilyl)-4-vinylazetidin-2-one, 26. A solution
of vinylazetidinone 25 (100 mg, 1.03 mmol) in dry dichloromethane
231.1745, calcd for C16H23O 231.1749.
J. Org. Chem. Vol. 73, No. 13, 2008 5019

Meiries and Marquez
(10 mL) was treated with anhydrous triethylamine (215 µL, 156
µg, 1.54 mmol), and TBSOTf (409 mg, 336 µL, 1.55 mmol) was
added slowly to the resulting solution. The reaction mixture was
stirred for 10 min, and the solvent was evaporated under reduced
pressure. The crude orange oil was immediately purified by flash
chromatography (silica gel, 10% ethyl acetate in 40-60 petroleum
ether) to afford the desired N-TBS-protected azetidinone 26 as a
5.27 (1H, d, J ) 10.3 Hz), 5.36 (1H, d, J ) 17.1 Hz), 5.86 (1H,
ddd, J ) 17.1, 10.3, 7.7 Hz); 13C NMR (100 MHz, CDCl3) δ
12.2, 27.9, 51.1, 61.2, 83.1, 118.7, 134.7, 147.8, 168.1; IR (thin
film) νmax ) 3086, 2979, 2934, 1808, 1724, 1339, 1156 cm-1
;
HRMS (CI) obsd (M + H)+ 212.1283, calcd for C11H18O3N
212.1287.
(2S,3S)-tert-Butyl 2-((1E,3E,5R,6R)-6-methoxy-3,5-dimethyl-
7-phenylhepta-1,3-dienyl)-3-methyl-4-oxoazetidine-1-carboxy-
late, 31, and (2R,3R)-tert-Butyl 2-((1E,3E,5R,6R)-6-methoxy-
3,5-dimethyl-7-phenylhepta-1,3-dienyl)-3-methyl-4-oxoazetidine-
1-carboxylate, 32. A solution of freshly purified methoxy diene
20 (40 mg, 0.174 mmol) and N-Boc-protected vinylazetidinone 29
(65 mg, 0.308 mmol) in dry toluene (2.5 mL) was treated with
second-generation Hoveyda-Grubbs catalyst 30 (23 mg, 20 mol%).
The resulting mixture was then refluxed for 22 h under anhydrous
conditions. The solvent was evaporated under reduced pressure to
yield a crude black viscous oil (130 mg) which was purified by
flash chromatography (silica gel, 0.5% TEA, 0-20% ethyl acetate
in 40-60 petroleum ether) to afford the desired heterodimers as a
1:1 mixture of diastereomers as a clear and very viscous yellowish
oil (50 mg, 67%).
The diastereomeric mixture (50 mg) was then loaded onto a
semipreparative HPLC under reversed-phase conditions as a DMSO
stock solution (C18 column, 65:35 acetonitrile/water) to attempt
the separation of the diastereomers. Compound 31 was isolated with
near-quantitative efficiency after 53 min (254 nm optimized wave-
length) (25 mg, 32% from diene 20). Compound 32 appears to have
decomposed as it was not detected either through the use of automatic
multiwavelength detectors or TLC analysis of individual fractions (75
min run time).
1
clear, colorless, and slightly viscous oil (215 mg, 99%): H NMR
(400 MHz, CDCl3) δ 0.17 (3H, s), 0.21 (3H, s), 0.94 (9H, s), 2.75
(1H, dd, J ) 15.4, 2.8 Hz), 3.29 (1H, dd, J ) 15.4, 5.6 Hz), 3.99
(1H, ddd, J ) 8.8, 5.6, 2.8 Hz), 5.16 (1H, dd, J ) 10.0, 0.8 Hz),
5.27 (1H, dq, J ) 17.1, 0.7 Hz), 5.84 (1H, ddd, J ) 17.1, 10.1, 8.9
Hz); 13C NMR (100 MHz, CDCl3) δ -5.7, -5.5, 18.9, 26.2, 45.4,
51.7, 117.5, 139.7, 172.3; IR (thin film) νmax ) 3475, 3084, 2954,
2929, 2858, 1749 cm-1; HRMS (CI) obsd (M + H)+ 212.1468,
calcd for C11H22ONSi 212.1471.
1-(tert-Butyldimethylsilyl)-3-methyl-4-vinylazetidin-2-one, 27.
A -78 °C solution of N-TBS-protected azetidinone 26 (7.73 g,
36.4 mmol) in anhydrous THF (400 mL) was treated with the slow
addition of n-BuLi (2.5 M, 28.4 mL, 710 mmol). The reaction was
then stirred for 10 min at -78 °C and was then quenched by
addition of iodomethane previously filtered through basic alumina
(7.52 mL, 17.2 g, 120.8 mmol). The reaction mixture was stirred
at -78 °C for a further 10 min and then worked up by the
sequential addition of methanol (12.9 mL) and satd aq am-
monium chloride (168.6 mL). The crude mixture was then filtered
through a pad of Celite and washed with diethyl ether (400 mL).
The solvent was removed under vacuum, and the crude yellow
oil (16.97 g) was purified by flash chromatography (silica gel,
10% ethyl acetate in 40-60 petroleum ether) to provide the pure
methylated azetidinone 27 as a clear, colorless, and slightly
31: 1H NMR (400 MHz, CDCl3) δ 1.03 (3H, d, J ) 6.7 Hz), 1.36
(3H, d, J ) 7.5 Hz), 1.48 (9H, s), 1.66 (3H, d, J ) 1.2 Hz), 2.60 (1H,
m), 2.66 (1H, d, J ) 7.5 Hz), 2.81 (1H, d, J ) 4.6 Hz), 2.95 (1H, m),
3.19 (1H, m), 3.24 (3H, s), 4.03 (1H, dd, J ) 8.1, 3.0 Hz), 5.45 (1H,
d, J ) 9.7 Hz), 5.54 (1H, dd, J ) 15.4, 8.1 Hz), 6.33 (1H, d, J ) 15.5
Hz), 7.17-7.29 (5H, m); 13C NMR (100 MHz, CDCl3) δ 12.3, 16.0,
28.0, 36.7, 38.2, 51.7, 58.7, 61.3, 77.2, 82.9, 86.8, 123.1, 126.0, 128.2,
1
viscous oil (6.43 g, 28.43 mmol, 78%): H NMR (400 MHz,
CDCl3) δ 0.14 (3H, s), 0.21 (3H, s), 0.93 (9H, s), 1.28 (3H, d,
J ) 7.4 Hz), 2.88 (1H, qd, J ) 7.4, 2.5 Hz), 3.56 (1H, dd, J )
8.9, 2.5 Hz), 5.13 (1H, dd, J ) 10.1, 1.0 Hz), 5.24 (1H, dq, J )
17.6, 0.6 Hz), 5.82 (1H, ddd, J ) 17.6, 10.1, 8.9 Hz); 13C NMR
(100 MHz, CDCl3) δ -5.6, -5.5, 13.2, 18.3, 26.2, 53.2, 60.7,
117.3, 139.2, 176.1; IR (thin film) νmax ) 3474, 3084, 2958,
2929, 2858, 1744 cm-1; HRMS (CI) obsd (M + H)+ 226.1626,
calcd for C12H24ONSi 226.1627.
129.4, 132.1, 137.4, 139.1, 139.2, 147.9, 168.5; IR (thin film) νmax
)
3422, 3029, 2976, 2931, 2875, 2362, 2342, 1810, 1723, 1333, 1157,
1104 cm-1; HRMS (CI) obsd (M + H)+ 212.1283, calcd for
C11H18O3N 212.1287.
3-Methyl-4-vinylazetidin-2-one, 28. A solution of N-TBS-
protected vinylazetidinone 27 (8.78 g, 38.95 mmol) in methanol (300
mL) was treated by the slow addition of potassium fluoride (4.22 g,
72.63 mmol) at 0 °C. The reaction mixture was stirred for 10 min,
and the solvent was evaporated under reduced pressure to yield a crude
orange/brown oil (5.57 g) which was purified by flash chromatography
(silica gel, 50% ethyl acetate in 40-60 petroleum ether) to afford the
pure desired azetidinone 28 as a clear, colorless, and slightly viscous
1
32: H NMR (400 MHz, CDCl3) δ 1.04 (3H, d, J ) 6.7 Hz),
1.35 (3H, d, J ) 7.4 Hz), 1.49 (9H, s), 1.64 (3H, d, J ) 1.2 Hz),
2.61 (1H, m), 2.69 (1H, d, J ) 7.5 Hz), 2.80 (1H, d, J ) 4.6 Hz),
2.94 (1H, m), 3.19 (1H, m), 3.23 (3H, s), 4.03 (1H, dd, J ) 8.1,
3.0 Hz), 5.46 (1H, d, J ) 9.8 Hz), 5.55 (1H, dd, J ) 15.4, 8.1 Hz),
6.34 (1H, d, J ) 15.5), 7.17-7.29 (5H, m); 13C NMR (100 MHz,
CDCl3) δ 12.7, 16.1, 28.0, 36.6, 38.1, 51.6, 58.6, 61.4, 77.3, 82.9,
86.9, 123.0, 126.1, 128.1, 129.3, 132.2, 137.2, 139.2, 147.8, 147.9,
168.4; IR (thin film) νmax ) 3422, 3029, 2976, 2931, 2875, 2362,
2342, 1810, 1723, 1333, 1157, 1104 cm-1; HRMS (CI) obsd (M
+ H)+ 212.1283, calcd for C11H18O3N 212.1287.
1
oil (3.77 g, 33.0 mmol 87%): H NMR (400 MHz, CDCl3) δ 1.34
(3H, d, J ) 7.4 Hz), 2.92 (1H, qdd, J ) 7.4, 2.3, 1.0 Hz), 3.72 (1H,
dm, J ) 7.2 Hz), 5.17 (1H, dappt, J ) 10.2, 0.9 Hz), 5.30 (1H, dappt,
J ) 17.1, 1.0 Hz), 5.92 (1H, ddd, J ) 17.1, 10.2, 7.1 Hz), 6.12 (1H,
s); 13C NMR (100 MHz, CDCl3) δ 12.7, 53.3, 58.2, 116.9, 137.1,
171.3; IR (thin film) νmax ) 3471, 3253, 3087, 3008, 2968, 2931, 2873,
1750, 1644, 1176, 926 cm-1; HRMS (CI) obsd (M + H)+ 112.0760,
calcd for C6H10ON 112.0762.
(2S,3S,4E,6E,8R,9R)-3-(tert-Butoxycarbonylamino)-9-methoxy-
2,6,8-trimethyl-10-phenyldeca-4,6-dienoic Acid (enantio-N-Boc-
ADDA), 7. A solution of N-Boc-protected lactam 31 (55 mg, 0.133
mmol) in THF (3 mL) was treated with aq LiOH (1.0 M, 0.60 mL,
0.60 mmol) at room temperature. The reaction was stirred at room
temperature until completion (5 h) and then quenched by the
sequential addition of water (2.4 mL) and glacial acetic acid (0.3
mL). The resulting mixture was extracted with diethyl ether (3 ×
20 mL), and the combined organics were dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure
to give a yellow oil (70 mg) which was purified by flash
chromatography (silica gel, 0-10% MeOH in DCM) to give
enantio-N-Boc-ADDA 7 as a clear and very viscous light yellowish
oil (58 mg, 100%). The spectral data for enantio-N-Boc ADDA
(3R,4R)-3-Methyl-2-oxo-4-vinylazetidine-1-carboxylic Acid
tert-Butyl Ester, 29. A solution of lactam 28 (47 mg, 0.423 mmol)
in anhydrous dichloromethane at room temperature (10 mL) was
sequentially treated with anhydrous triethylamine (56 µL, 40.6
µg, 0.40 µmol), DMAP (50 mg, 0.41 mmol), and (Boc)2O (96
mg, 0.44 mmol). The resulting reaction mixture was stirred
overnight and then concentrated under reduced pressure. The
resulting crude yellow oil (151 mg) was purified by flash chro-
matography (silica gel, 0.5% TEA, 10% ethyl acetate in 40-60
petroleum ether to give the pure desired N-Boc-protected lactam
1
1
29 as a clear and colorless viscous oil (89 mg, 100%): H NMR
matched that reported for N-Boc ADDA: H NMR (400 MHz,
(400 MHz, CDCl3) δ 1.34 (3H, d, J ) 7.5 Hz), 1.48 (9H, s),
2.91 (1H, qd, J ) 7.5, 3.0 Hz), 3.96 (1H, dd, J ) 7.7, 3.0 Hz),
CDCl3) δ 1.03 (3H, d, J ) 6.7 Hz), 1.04 (3H, d, J ) 6.7 Hz), 1.25
(3H, d, J ) 7.4 Hz), 1.45 (3H, s), 1.61 (3H, s), 2.57-2.81 (4H,
5020 J. Org. Chem. Vol. 73, No. 13, 2008

ConVergent Synthesis of (2R,3R,8R,9R)-N-Boc-ADDA
m), 3.19 (1H, m), 3.23 (3H, s), 4.39 (1H, bs), 5.25 (1H, bs), 5.39
(1H, d, J ) 9.8 Hz), 5.48 (1H, dd, J ) 15.7, 6.1 Hz), 6.20 (1H, d,
J ) 15.6 Hz), 7.17-7.29 (5H, m); 13C NMR (100 MHz, CDCl3) δ
12.7, 14.6, 16.2, 28.4, 36.7, 38.3, 44.1, 54.1, 58.6, 79.8, 87.0, 125.1,
125.9, 128.2, 129.4, 132.5, 135.9, 136.5, 139.2, 139.4, 155.5, 179.4;
[R]23D +15.1 (c ) 1.0, CHCl3); IR (thin film) νmax ) 3419, 3334,
3029, 2972, 2929, 2605, 2534, 1709, 1169, 740, 701 cm-1; HRMS
(CI) obsd (M + H)+ 432.2749, calcd for C25H38O5N 432.2750.
the University of Glasgow for financial support. We also
acknowledge Dr. Verena Bo¨hrsch and Dr. Richard Hartley for
useful discussions.
Supporting Information Available: Spectral data of the
described compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. S.M. thanks the EPSRC for a postgraduate
studentship. R.M. is grateful to Dr. Ian Sword, the EPSRC, and
JO800574G
J. Org. Chem. Vol. 73, No. 13, 2008 5021