De novo asymmetric synthesis of anamarine and its analogues

Article abstract of DOI:10.1021/jo051681p

The enantioselective synthesis of anamarine has been achieved in 21 steps. The route relies on enantio- and regioselective Sharpless dihydroxylation of dienoate ester and zinc borohydride reduction to establish the C-8-C-11 stereochemistry. A diastereosel

Full text of DOI:10.1021/jo051681p

De Novo Asymmetric Synthesis of Anamarine and Its Analogues
Dong Gao and George A. O’Doherty*
Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506
George.ODoherty@mail.wvu.edu
Received August 9, 2005
The enantioselective synthesis of anamarine has been achieved in 21 steps. The route relies on
enantio- and regioselective Sharpless dihydroxylation of dienoate ester and zinc borohydride
reduction to establish the C-8-C-11 stereochemistry. A diastereoselective Leighton allylation
established the desired C-5 stereochemistry. The route has also been used to prepare two
diastereoisomers of anamarine in 14 steps.
Introduction
For the last five years, we have been interested in a
class of natural products with a skipped, 1,3-polyol/5,6-
dihydro-2H-pyran-2-one structural motif which possess
a wide range of biological properties.1,2 This interest has
met with some degree of success in terms of total
synthesis.3 As a result of these efforts, we became
interested in the synthesis of natural products with a 1,2-
polyol/5,6-dihydro-2H-pyran-2-one structural motif. Thus,
we targeted the antitumor pyranone natural product
anamarine for synthesis (1a, Figure 1).
The 5,6-dihydro-2H-pyran-2-one containing natural
product, anamarine (1a), was isolated from the flowers
and leaves of a Peruvian hyptis. Other members of this
R,â-unsaturated lactone class of natural products include
spicigerolide (2), hyptolide (3), and synrotolide (4) (Figure
1), which possess an array of properties ranging from
cytotoxicity against human tumor cells to antibacterial
and/or antifungal activity.4
FIGURE 1. The anamarine-type R,â-unsaturated lactones.
in preparing several stereoisomers of anamarine via
asymmetric catalysis.6 Recently, we demonstrated the
viability of this approach for the preparation of two
epimers of anamarine.5f Key to this approach was the
discovery of an expedient and practical synthesis of C-6-
substituted galacto-sugars from simple achiral precursors
with complete stereocontrol (5-6, Scheme 1).7 Herein,
we report the full account of this approach and detail the
application for the synthesis of anamarine.
Numerous synthetic approaches to this class of mol-
ecules have been reported.5 In contrast to these previous
syntheses, which derived their absolute and relative
stereochemistry from carbohydrates,5 we were interested
(5) (a) Diaz-Oltra, S.; Murga, J.; Falomir, E.; Carda, M.; Marco, J.
A. Tetrahedron 2004, 60, 2979-2985. (b) Falomir, E.; Murga, J.; Ruiz,
P.; Carda, M.; Marco, J. A. J. Org. Chem. 2003, 68, 5672-5676. (c)
Lorenz, K.; Lichtenthaler, F. W. Tetrahedron Lett. 1987, 28, 6437-
6440. (d) Valverde, S.; Herradon, A.; Herradon, B.; Babanal, R. M.;
Marrtin-Lomas, M. Tetrahedron 1987, 43, 3499-3504. (e) Lichtentha-
ler, F. W.; Lorenz, K.; Ma, W. Tetrahedron Lett. 1987, 28, 47-50. (f)
Gao, D.; O’Doherty, G. A. Org. Lett. 2005, 7, 1069-1072.
(6) Migual Carda and Alberto Marco noted that various stereoiso-
mers of spicigerolide (2) have improved cytotoxicity against several
cancer cell lines; see ref 5b.
(7) (a) Ahmed, Md. M.; Berry, B. P.; Hunter, T. J.; Tomcik, D. J.;
O’Doherty, G. A. Org. Lett. 2005, 7, 745-748. (b) Ahmed, Md. M.;
O’Doherty, G. A. Tetrahedron Lett. 2005, 46, 3015-3019.
(1) Jodynis-Liebert, J.; Murias, M.; Bloszyk, E. Planta Med. 2000,
66, 199.
(2) Drewes, S. E.; Schlapelo, B. M.; Horn, M. M.; Scott-Shaw, R.;
Sandor, O. Phytochemistry 1995, 38, 1427.
(3) (a) Smith, C. M.; O’Doherty, G. A. Org. Lett. 2003, 5, 1959-1962.
(b) Garaas, S. D.; Hunter, T. J.; O’Doherty, G. A. J. Org. Chem. 2002,
67, 2682-2685. (c) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3,
2777.
(4) (a) Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garcia-
Rojas, C. M. Tetrahedron 2001, 57, 47-53. (b) Pereda-Miranda, R.;
Hernandez, L.; Villavicencio, M. J.; Novelo, M.; Ibarra, P.; Chai, H.;
Pezzuto, J. M. J. Nat. Prod. 1993, 56, 583-593.
10.1021/jo051681p CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/21/2005
9932
J. Org. Chem. 2005, 70, 9932-9939

Asymmetric Synthesis of Anamarine and Its Analogues
SCHEME 1. Retrosynthetic Analysis of
Anamarine and Its Analogues
SCHEME 2. Initial Synthesis of Ester 6b
Results and Discussion
We envisioned that the lactone rings of anamarine 1a
could be prepared by a ring-closing metathesis reaction8
of triene 5a (Scheme 1), which could be obtained from
6a by a reduction, a Leighton allylation,9,10 and acylation.
Finally, it was envisioned that the C-8 through C-11
tetrol stereochemistry of 6a could be established by
applying two Sharpless dihydroxylations followed by an
inversion at C-10.11 By simply skipping the inversion at
C-10 and performing a diastereo-divergent allylation
reaction, two diastereomers of anamarine (1b and 1c)
should be produced.
In our initial approach to 10-epi-anamarine (1b), we
targeted the bis-acetonide 6b as a key intermediate
(Scheme 2). We envisioned preparing 6b from trienoate
8, which was easily prepared by a Wittig reaction of
commercially available 2,4-hexadienal and ylide (EtO2-
CCHdPPh3). Exposing trienoate 8 to the Sharpless
dihydroxylation protocol yielded a diol, which was pro-
tected as the acetonide to give dienoate 9 in a good yield
(72% for two steps) and enantiomeric excess (90% ee). A
second Sharpless dihydroxylation on dienoate 9 was
preformed using the stereochemically matched ligand
system ((DHQD)2PHAL). The desired diol 10b was
formed with excellent diastereocontrol; however, to our
surprise, it was also formed with a significant amount
of the undesired regioisomer 10a. The two regioisomers
10a and 10b were obtained in a 1:1 ratio. To our delight,
the desired regioisomer 10b was separated by chroma-
tography and protected as bis-acetonide 6b.
Unfortunately, removing the acetonide protecting group
had no positive effect on the regioselectivity of the second
dihydroxylation.12 This loss of regiocontrol is not solely
due to the ligand. It also occurred when 9 was dihydrox-
ylated under ligandless conditions (i.e., when 9 was
exposed to OsO4/NMO, four diastereomeric tetrol prod-
ucts were produced).
In a search for better regioselectivity in the synthesis
of ester 6b, we investigated the bis-dihydroxylation of
the commercially available ethyl sorbate (7) (Scheme 3).
Thus, ethyl sorbate (7) was enantioselectively dihydrox-
ylated (1 mol % OsO4 and 2 mol % (DHQ)2PHAL) and
SCHEME 3. Improved Synthesis of Ester 6b
(8) For a review on ring-closing metathesis reactions, see: (a)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b) Deiters, A.;
Martin, S. F. Chem. Rev. 2004, 104, 2199-2238. For other uses of this
pyranone formation in synthesis, see ref 3 and: (c) Pradaux, F.;
Bouzbouz, S. Org. Lett. 2001, 3, 2233-2235. (d) Ghosh, A. K.; Wang,
Y.; Kim, J. T. J. Org. Chem. 2001, 66, 8973. (e) Reddy, M. V. R.; Yucel,
A. J.; Ramachandran, P. V. J. Org. Chem. 2001, 66, 2512. (f) Wang,
Y.-G.; Kobayashi, Y. Org. Lett. 2002, 4, 4615. (g) Mizutani, H.;
Watanabe, M.; Honda, T. Tetrahedron 2002, 58, 8929. (h) Trost, B.
M.; Yeh, V. S. C. Org. Lett. 2002, 4, 3513. (i) Falomir, E.; Murga, J.;
Carda, M.; Marco, J. A. Tetrahedron Lett. 2003, 44, 539.
(9) Kubota, K.; Leighton, J. Angew. Chem., Int. Ed. 2003, 42, 946-
948.
(10) We initially considered the use of the catalytic asymmetric
allylation reagent developed by Keck but were dissuaded by its use of
stoichiometric tin. See: (a) Keck, G. E.; Krishnamurthy, D. Org. Synth.
1997, 75, 12. (b) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem.
Soc. 1993, 115, 8467-8468.
(11) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(12) In contrast to our results for acetonide 14 and its corresponding
diol, Smith observed excellent regiocontrol (>10:1) in the dihydroxyl-
ation of related substituted epoxytrienoates. Similarly, they observed
no significant loss of stereocontrol in the mismatched (slower) case.
See: Smith, A. B., III; Walsh, S. P.; Frohn, M.; Duffey, M. O. Org.
Lett. 2005, 7, 139-142.
J. Org. Chem, Vol. 70, No. 24, 2005 9933

Gao and O’Doherty
SCHEME 4. Synthesis of Epimeric Ester 6a
the corresponding diol was protected to give acetonide
11 in good yield (74% for two steps) and enantiomeric
excess (80% ee).7a Once again, the R,â-unsaturated ester
11 was dihydroxylated in a diastereomerically matched
sense,5f with the pseudoenantiomeric reagent (2 mol %
OsO4, 4 mol % (DHQD)2PHAL, 3 equiv of K3Fe(CN)6, 3
equiv of K2CO3, and 1 equiv of MeSO2NH2). This dia-
stereoselectively matched reaction gave a diol (diaster-
eomeric ratio ) 10:1), which was protected as the
acetonide 12 (66% yield for two steps). It is worth noting
that as a result of performing the second dihydroxylation
(11-12) with a diastereomerically matched chiral reagent
system, the bis-acetonide 12 was isolated with greater
enantiomeric purity (>96% ee) than the initial acetonide
11.13
Having established the relative and absolute stereo-
chemistry of 10-epi-anamarine 1b in 12, we looked to
convert ester 12 into R,â-unsaturated ester 6b. This was
accomplished by an exhaustive reduction of ester 12 with
DIBALH (3.0 equiv, 93%) followed by a Swern oxidation,
providing aldehyde 13 (82% yield, two steps). Finally, a
Wittig reaction of aldehyde 13 with EtO2CCHdPPh3
provided the desired ester 6b in 81% yield.
To approach the correct diastereomer 6a, we returned
to the asymmetric synthesis of the diastereomeric alde-
hyde 21 from the ethyl sorbate 7 (Scheme 4). As we
previously described, ethyl sorbate was enantioselectively
dihydroxylated and the corresponding diol was converted
into cyclic carbonate 14 in good yield (74% for two steps)
and enantiomeric excess (80% ee).7b Treatment of carbon-
ate 14 with a catalytic amount of palladium(0) (0.5 mol
%/2 mol % PPh3) and p-methoxyphenol as the nucleophile
provided the protected alcohol 15 in 91% yield. The other
hydroxyl group was protected as silyl ether to give 16.
Enoate 16 was then dihydroxylated in a diastereomeri-
cally matched sense,7b with the matched reagent (2 mol
% OsO4, 4 mol % (DHQD)2PHAL, 3 equiv of K3Fe(CN)6,
3 equiv of K2CO3, and 1 equiv of MeSO2NH2) to diaste-
reoselectively give a diol which was protected as the
acetonide 17 (66% yield for two steps). As a result of
performing the second dihydroxylation (16-17) with a
diastereomerically matched chiral reagent system, the
acetonide 17 was isolated with greater enantiomeric
purity (>96% ee) than the initial diol.
20 in good yield. With the relative and absolute tetrol
stereochemistry established in 20, we next looked to
homologate ester 20 into enaote 6a. Exhaustive reduction
of ester 20 with DIBALH (3.0 equiv, 93%) followed by a
Swern oxidation (88%) provided aldehyde 21 in 82% yield
for two steps. A Wittig reaction of aldehyde 21 with
corresponding ylide (EtO2CCHdPPh3) provided a 1:1
ratio of Z/E isomers of acetonide 6a,c in 86% yield, which
were inseparable.14
We next looked into the inversion of the stereochem-
istry at C-10. Because our initial efforts to accomplish
this with Mitsunobu chemistry met with little success,
we turned to an oxidation/reduction strategy. Selective
deprotection of the p-methoxyphenoxy ether (CAN) fol-
lowed by Dess-Martin periodinane oxidation provided
ketone 18. Cleavage of the silyl ether with benzoic acid
and TBAF gave alcohol 19. Sodium borohydride reduction
of the TBS-protected ketone 18 gave two diastereomers
in a 4:1 ratio. Unfortunately, the major diastereomer was
the undesired syn-diol. So, we turned to a chelation-
controlled reduction. Treating the deprotected ketone 19
with zinc borohydride gave the anti-diol as the major
product in a 5:1 ratio. The anti-diol was then treated with
2,2-dimethoxypropane and CSA, providing bis-acetonide
In an attempt to shorten the route to ester 6a, we tried
oxidizing the C-10 alcohol before the asymmetric dihy-
SCHEME 5. Alternative Approach to Ester 6a
(14) The lack of E/Z selectivity (1:1) in the Wittig reaction with
aldehyde 21 is quite surprising when compared to the nearly identical
Wittig reaction with the C-5 diastereomeric aldehyde 13, where the E
isomer 6b was formed with almost 10:1 selectivity. Although we cannot
offer an explanation for this result, we did find this result to be
reproducible.
(13) Although the conversion of 10-11 is a diastereoselective
matched reaction with the (DHQD)2PHAL/OsO4 reagent system, the
reaction occurs at a significantly slower rate and, as such, higher
catalyst loading is required (2% OsO4 and 4% (DHQD)2PHAL, see
Scheme 3).
9934 J. Org. Chem., Vol. 70, No. 24, 2005

Asymmetric Synthesis of Anamarine and Its Analogues
SCHEME 6. Installation of the Pyranone Ring in
26a,b
SCHEME 7. Installation of the Pyranone Ring in
26c
(>99% ee and dr).15,16 The allylic alcohols 24a,b were
coupled with DCC (4 equiv) and acrylic acid (4 equiv) in
CH2Cl2, providing trienes 5a and 5b in 83% and 78%
yields, respectively. We next turned to the use of a ring-
closing metathesis reaction to form the lactone ring. This
was easily implemented by exposure of a refluxing CH2-
Cl2 solution of the trienes 5a,b to the Grubbs catalyst
28 (10 mol %), resulting in a clean cyclization to dihy-
dropyrans 26a and 26b in 77% and 82% yields, respec-
tively.
The other diastereomeric series can be made by simply
switching to the enantiomeric Leighton reagent ((R,R)-
ent-27, Scheme 7). Thus, exposing aldehyde 24b to the
enantiomeric Leighton reagent, (R,R)-ent-27, yielded a
diastereomerically pure allylic alcohol 25c (95%), which,
as before, could be converted into lactone 26c via an
acylation and metathesis sequence (61% yield for the two
steps).
droxylation (Scheme 5). The oxidation of the allylic
alcohol in 22 with TEMPO was accomplished after initial
TBS protection of the C-5 alcohol (67% for two steps). To
our surprise, the dihydroxylation reaction only gave a 3:1
mixture of diastereomers 23a and 23b, respectively (75%
yield for the two isomers). Although this is a shorter
sequence, because of the difficulty in separating the
diastereomers 23a and 23b, we found it easier to prepare
material by the previous route (Scheme 4).
The problem associated with inseparable double-bond
isomers 6a and 6c was solved when the esters were
converted into aldehydes 24a and 24c. This was ac-
complished by a reduction/oxidation sequence. Exposure
of a THF solution of two isomers, 6a,c, with 3.0 equiv of
DIBALH at -78 °C provided allylic alcohol (Scheme 6),
which without purification was oxidized with MnO2 to
give aldehyde 24a,c in good yield (82% for two steps). At
the aldehyde stage, the two isomers were separable. More
importantly, the undesired isomer 24c was converted
back to the desired isomer upon treatment with 10 mol
% TFA in CH2Cl2 (80% of a 10:1 ratio). By an identical
sequence, the C-10 diastereomer 6b was converted into
aldehyde 24b (82%).
To complete the synthesis of anamarine 1a and its two
epimers, 1b,c (Scheme 8), all that remains is to deprotect
the acetonides and acylate the resulting tetrols. We found
that this was most easily accomplished by heating the
SCHEME 8. Synthesis of Anamarine 1a and
Epimers 1b,c
With the two desired aldehydes 24a,b in hand, we
turned to the installation of the pyranone portion of the
natural product. We envisioned that a diastereoselective
allylation of aldehydes 24a,b could be achieved by using
either enantiomer of the easily prepared Leighton allyl
silane reagents (S,S)-279 (Schemes 6 and 7). This was
accomplished by simply adding a solution of either
aldehyde 24a or 24b to the allylsilane reagent (S,S)-27
(0.2 M in CH2Cl2) at -10 °C to give allylic alcohols 25a,b
in 91% and 92% yields with near complete stereocontrol
(15) Previous approaches to this class of pyranone natural products
used the Brown AllylBIpc2 reagent for this transformation; see ref 5a-
d. We have found that the Leighton reagent works equally well in
terms of stereochemical outcome and allows for a significantly simpler
product isolation procedure; see ref 9.
(16) All enantioexcesses were determined by examining the 1H NMR
of the corresponding Mosher esters. See: Sullivan, G. R.; Dale, J. A.;
Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
J. Org. Chem, Vol. 70, No. 24, 2005 9935

Gao and O’Doherty
EtOAc); [R]25 -18° (c 1, CHCl3); IR (neat, cm-1) 3474, 2931,
three diastereomeric lactones 26a-c in 10% aqueous
hydrochloric acid in THF for 10 min at 65 °C. Because of
the high polarity, the crude tetrol products were directly
acylated by removal of solvent and addition of pyridine,
acetic anhydride, and DMAP. This two-step/one-pot
protocol provided excellent yields of anamarine 1a (85%
for two steps) and its two diastereomers 1b,c (86% and
82% yields).
D
1736, 1506; 1H NMR (CDCl3, 270 MHz) δ 6.93 (d, J ) 9.2 Hz,
2H), 6.78 (d, J ) 9.2 Hz, 2H), 4.35-4.19 (m, 6H), 4.08 (s, 1H),
3.71 (s, 3H), 3.28 (d, J ) 8.7 Hz, 1H), 1.32 (d, J ) 6.4 Hz, 3H),
1.27 (t, J ) 7.2 Hz, 3H), 0.85 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H);
13C NMR (CDCl3, 62.5 MHz) δ 173.3, 154.3, 151.5, 117.4, 117.4,
114.5, 114.5, 76.6, 71.9, 70.2, 68.3, 61.5, 55.3, 25.5, 25.5, 25.5,
17.6, 17.0, 14.0, -5.05, -5.40; HRMS (CI) calcd for [C21H36O7-
Si + Na]+ 451.2123, found 451.2142.
(4S,5R)-Ethyl-5-(1R,2S)-(2-methoxyphenoxy-1-tert-bu-
tyldimethylsiloxy)-2,2-dimethyl-1,3-dioxolane-4-car-
boxyate (17). To a solution of A (6.28 g, 14.7 mmol) in 20 mL
of CH2Cl2 was added 2,2-dimethoxypropane (9.09 mL, 73.35
mmol) and CSA (137 mg, 4 mol %, 0.59 mmol) at room
temperature. In 36 h, the reaction was quenched by adding
saturated NaHCO3. The aqueous layer was separated and
extracted with Et2O, and the combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and con-
centrated to afford the crude product. Flash chromatography
on silica gel (8:2 (v/v) hexane/EtOAc) provided compound 17
(5.57 g, 81% yield) as a colorless oil: Rf ) 0.39 (7:3 (v/v) hexane/
Conclusion
In summary, an enantioselective synthesis of anama-
rine has been developed. This highly enantio- and dia-
stereocontrolled route illustrates the utility of an iterative
Sharpless Asymmetric Dihydroxylation reaction and a
Leighton allylation sequence. Although this approach to
anamarine is rather long (21 steps), this route provides
diastereomers of anamarine in significantly less steps (14
steps). This approach provided anamarine in 8% overall
yield and provided its two diastereomers in 14% and 13%
yields. It is also worth noting that these new routes start
from achiral sources. Further application of this approach
to other members of this class of natural products is
ongoing.
EtOAc); [R]25 +6° (c 1, CHCl3); IR (neat, cm-1) 2932, 1749,
D
1
1506; H NMR (CDCl3, 270 MHz) δ 6.91 (d, J ) 9.2 Hz, 2H),
6.76 (d, J ) 8.9 Hz, 2H), 4.65 (d, J ) 5.9 Hz, 1H), 4.56 (dd,
J ) 3.9, 6.2 Hz, 1H), 4.27-4.15 (m, 3H), 4.05 (dd, J ) 6.5, 6.2
Hz, 1H), 3.72 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H), 1.26 (t, J ) 7.2
Hz, 3H), 1.23 (d, J ) 5.9 Hz, 3H), 0.83 (s, 9H), 0.05 (s, 3H),
-0.05 (s, 3H); 13C NMR (CDCl3, 62.5 MHz) δ 171.3, 153.8,
153.5, 117.2, 117.2, 114.1, 114.1, 111.2, 82.8, 78.6, 75.6, 68.2,
Experimental Section17
_
61.3, 55.5, 26.7, 25.7, 25.7, 25.7, 25.6, 20.1, 17.9, 14.0, 4.82,
(E,4S,5S)-Ethyl-4-(4-methoxyphenoxy)-5-(tert-butyldi-
methylsiloxy)-2-enoate (16). To a solution of alcohol 15 (13.2
g, 47.1 mmol) in 10 mL of dry DMF was added imidazole (9.6
g, 141.3 mmol) and TBSCl (10.2 g, 68.3 mmol) at room
temperature. The reaction was stirred for 2 h, and then the
reaction mixture was directly purified by flash chromatography
on silica gel (7:3 (v/v) hexane/EtOAc) to provide compound 16
(18.5 g, 100% yield) as a colorless oil: Rf ) 0.60 (7:3 (v/v)
-4.82; HRMS (CI) calcd for [C24H40O7Si + Na]+ 491.2436,
found 491.2453.
(4S,5R)-Ethyl-5-(1R,2S)-(2-hydroxy-1-tert-butyldimeth-
ylsiloxy)-2,2-dimethyl-1,3-dioxolane-4-carboxyate (B).18
To a solution of ether 17 (2.70 g, 5.77 mmol) in 60 mL of CH3-
CN/H2O (4:1) was added CAN (6.32 g, 11.53 mmol) at 0 °C.
After 10 min, the mixture was partitioned between EtOAc and
brine. The organic layer was washed with saturated NaHCO3
and brine, dried over anhydrous Na2SO4, and concentrated to
afford the crude product. Flash chromatography on silica gel
(8:2 (v/v) hexane/EtOAc) provided compound B (1.3 g, 61%
yield) as a yellow oil: Rf ) 0.29 (8:2 (v/v) hexane/EtOAc); IR
hexane/EtOAc); IR (neat, cm-1) 2930, 1720; [R]25 -15° (c 1,
D
1
CHCl3); H NMR (CDCl3, 270 MHz) δ 7.02 (dd, J ) 4.5, 15.8
Hz, 1H), 6.78 (s, 2H), 6.77 (s, 2H), 6.06 (dd, J ) 1.5, 15.8 Hz,
1H), 4.58 (ddd, J ) 1.5, 4.2, 4.2 Hz, 1H), 4.14 (dq, J ) 1.0, 7.2
Hz, 1H), 4.07 (q, J ) 7.2 Hz, 1H), 4.05 (q, J ) 7.2 Hz, 1H),
3.69 (s, 3H), 1.23 (t, J ) 7.2 Hz, 3H), 1.16 (d, J ) 6.2 Hz, 3H),
0.87 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 62.5
MHz) δ 165.7, 154.0, 151.7, 144.0, 123.0, 116.5, 116.5, 114.3,
114.3, 81.3, 69.5, 60.1, 55.2, 25.6, 25.6, 25.6, 18.8, 17.8, 14.0,
-4.91, -4.95; HRMS (CI) calcd for [C21H34O5Si + Na]+
417.2068, found 417.2086.
(neat, cm-1) 3442, 2932, 1749; [R]25 +12° (c 1, CHCl3); 1H
D
NMR (CDCl3, 270 MHz) δ 4.48 (d, J ) 5.9 Hz, 1H), 4.21 (q,
J ) 7.2 Hz, 2H), 4.18 (d, J ) 5.9 Hz, 1H), 4.05 (dq, J ) 1.5,
6.2 Hz, 1H), 3.26 (ddd, J ) 1.7, 9.2, 9.2 Hz, 1H), 2.41 (d, J )
9.6 Hz, 1H), 1.42 (s, 3H), 1.38 (s, 3H), 1.27 (t, J ) 7.2 Hz, 3H),
1.21 (d, J ) 6.2 Hz, 3H), 0.88 (s, 9H), 0.08 (s, 6H); 13C NMR
(CDCl3, 62.5 MHz) δ 171.2, 111.5, 78.3, 77.8, 76.2, 67.1, 61.3,
27.2, 25.8, 25.7, 25.7, 25.7, 20.3, 17.9, 14.1, -4.32, -5.07;
HRMS (CI) calcd for [C17H34O6Si + Na]+ 385.2017, found
385.2006.
(2S,3S,4S,5S)-Ethyl-4-(4-methoxyphenoxy)-5-(tert-bu-
tyldimethylsiloxy)-2,3-dihydroxyhexanoate (A).18 Into a
250 mL round-bottom flask was added 50 mL of t-BuOH, 50
mL of water, K3Fe(CN)6 (19.7 g, 60.0 mmol), K2CO3 (8.3 g, 60.0
mmol), MeSO2NH2 (1.9 g, 20.0 mmol), (DHQD)2PHAL (321 mg,
0.4 mmol, 2 mol %), and OsO4 (51 mg, 0.2 mmol, 1 mol %).
The mixture was stirred at room temperature for about 15 min
and then cooled to 0 °C. To this solution was added a solution
of 16 (7.8 g, 20.0 mmol) in 5 mL of CH2Cl2, and the reaction
was stirred vigorously at 0 °C for 20 h. The reaction was
quenched with solid sodium sulfite at room temperature. Then
the mixture was filtered through a pad of Celite/florisil and
eluted with (2 × 80 mL) ethyl acetate. The combined organic
layers were washed with 2 N KOH and brine and dried over
anhydrous sodium sulfate. The solvent was removed in vacuo.
The crude product was purified by flash chromatography on
silica gel (7:3 (v/v) hexane/EtOAc) yielding compound A (7.3
g, 85% yield) as a viscous oil: Rf ) 0.39 (7:3 (v/v) hexane/
(4S,5R)-Ethyl-5-(1R)-(2-oxo-1-tert-butyldimethylsiloxy)-
2,2-dimethyl-1,3-dioxolane-4-carboxyate (18). To a solu-
tion of alcohol B (1.22 g, 3.36 mmol) in 25 mL of CH2Cl2 was
added Dess-Martin periodinane (1.85 g, 4.40 mmol) at room
temperature. After 3 h, the mixture was diluted with hexanes
and stirred with a solution of NaS2O3 for 30 min. The aqueous
layer was extracted with EtOAc, and the combined organic
layers were washed with brine, dried over anhydrous Na2SO4,
and concentrated to afford the crude product. Flash chroma-
tography on silica gel (8:2 (v/v) hexane/EtOAc) provided
compound 18 (1.20 g, 99% yield) as a colorless oil: Rf ) 0.40
(8:2 (v/v) hexane/EtOAc); IR (neat, cm-1) 2989, 1748; [R]25
D
1
+14° (c 1, CHCl3); H NMR (CDCl3, 270 MHz) δ 5.10 (d, J )
5.7 Hz, 1H), 4.81 (d, J ) 5.7 Hz, 1H), 4.50 (q, J ) 6.7 Hz, 1H),
4.25 (q, J ) 7.2 Hz, 2H), 1.45 (s, 3H), 1.44 (s, 3H), 1.35 (d,
J ) 6.9 Hz, 3H), 1.29 (t, J ) 7.2 Hz, 3H), 0.90 (s, 9H), 0.12 (s,
3H), 0.09 (s, 3H); 13C NMR (CDCl3, 62.5 MHz) δ 207.2, 170.2,
112.9, 78.6, 75.5, 72.4, 61.6, 26.5, 26.0, 25.7, 25.7, 25.7, 19.9,
18.1, 14.0, -4.89, -5.08; HRMS (CI) calcd for [C17H32O6Si +
Na]+ 383.1860, found 383.1872.
(17) Experimental procedures for the synthesis of anamarine are
presented in the Experimental Section. Complete experimental pro-
cedures and spectral data for all compounds are presented in the
Supporting Information.
(18) These structures are not shown in the text.
9936 J. Org. Chem., Vol. 70, No. 24, 2005

Asymmetric Synthesis of Anamarine and Its Analogues
(4S,5R)-Ethyl-5-(1R)-(2-oxo-1-hydroxy)-2,2-dimethyl-
1,3-dioxolane-4-carboxyate (19). To a solution of silyl ester
18 (298 mg, 0.83 mmol) in 4 mL of THF was added benzonic
acid (202 mg, 1.65 mmol) and TBAF (1.65 mL of a 1.0 M
solution in THF) at room temperature. After 2 h, the mixture
was diluted with EtOAc and quenched with saturated NaH-
CO3. The aqueous layer was extracted with EtOAc, and the
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated to afford the crude
product. Flash chromatography on silica gel (8:2 (v/v) hexane/
EtOAc) provided compound 19 (151 mg, 90% yield) as a
14.8, 14.2; HRMS (CI) calcd for [C14H24O6 + Na]+ 311.1465,
found 311.1459.
(2S,3R)-2,2-Dimethyl-5-((4′S,5′S)-2′,2′,5-trimethyl-1′,3′-
dioxolan-4′-yl)-1,3-dioxolane-4-carboxyate (E).18 To a so-
lution of ester 20 (100 mg, 0.35 mmol) in 1 mL of THF was
added DIBAL-H (1.0 mL, 1.0 M in hexanes, 1.0 mmol)
_
dropwise at 78 °C. After 1 h, the reaction was quenched by
adding 1 mL of acetone and 3 mL of 20% sodium potassium
tartrate solution. The mixture was stirred for 30 min. The
aqueous layer was extracted with Et2O, and the combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated to afford the crude product. Flash
chromatography on silica gel (7:3 (v/v) hexane/EtOAc) provided
compound E (75 mg, 89% yield) as a colorless oil: Rf ) 0.21
(7:3 (v/v) hexane/EtOAc); IR (neat, cm-1) 3369, 2989, 1456;
colorless oil: Rf ) 0.25 (8:2 (v/v) hexane/EtOAc); IR (neat, cm-1
)
1
3453, 2986, 1744; [R]25 +32° (c 1, CHCl3); H NMR (CDCl3,
D
270 MHz) δ 4.93 (d, J ) 6.5 Hz, 1H), 4.62 (d, J ) 6.4 Hz, 1H),
4.56 (q, J ) 6.8 Hz, 1H), 4.26 (q, J ) 7.2 Hz, 2H), 1.49 (s, 3H),
1.45 (s, 3H), 1.42 (d, J ) 6.9 Hz, 3H), 1.29 (t, J ) 7.2 Hz, 3H);
13C NMR (CDCl3, 62.5 MHz) δ 209.3, 169.8, 113.4, 79.9, 76.2,
71.5, 62.1, 26.3, 25.7, 19.3, 14.0; HRMS (CI) calcd for [C11H18O6
+ Na]+ 269.0996, found 269.1007.
[R]25 +60° (c 1, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 4.38
D
(dq, J ) 6.5, 6.5 Hz, 1H), 4.04 (ddd, J ) 3.5, 3.5, 8.7 Hz, 1H),
3.96 (dd, J ) 1.5, 6.5 Hz, 1H), 3.83 (dd, J ) 1.5, 8.7 Hz, 1H),
3.58 (ddd, J ) 3.5, 7.4, 11.4 Hz, 1H), 2.37 (bs, 1H), 1.48 (s,
3H), 1.41 (s, 3H), 1.38 (s, 3H), 1.36 (d, J ) 6.5 Hz, 3H), 1.32
(s, 3H); 13C NMR (CDCl3, 62.5 MHz) δ 109.3, 108.2, 77.5, 75.3,
75.2, 72.8, 60.8, 27.1, 27.0, 26.6, 25.4, 15.0; HRMS (CI) calcd
for [C12H22O5 + Na]+ 269.1359, found 269.1353.
(4S,5R)-Ethyl-5-(1S,2S)-(1,2-dihydoxypropyl)-2,2-dimeth-
yl-1,3-dioxolane-4-carboxyate (C).18 (4S,5R)-Ethyl-5-(1R,-
2S)-(1,2-dihydoxypropyl)-2,2-dimethyl-1,3-dioxolane-4-
carboxyate (D).18 To a solution of alcohol 19 (99 mg, 0.40
mmol) in 5 mL of ether was added Zn(BH4)2 (4 mL, 0.39 mmol)
at -10 °C. After 2.5 h, the mixture was quenched with
saturated NaHCO3. The aqueous layer was extracted with
EtOAc, and the combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and concentrated to afford
the crude mixture of regioisomers (C/D ) 5/1 determined by
1H NMR). Flash chromatography on silica gel (8:2 (v/v) hexane/
EtOAc) provided two pure regioisomers (75 mg, 75% combined
yield), C (62 mg, 63% yield) as a colorless oil and D (12 mg,
12%) as a colorless oil.
(2S,3R)-2,2-Dimethyl-5-((4′S,5′S)-2′,2′,5-trimethyl-1′,3′-
dioxolan-4′-yl)-1,3-dioxolane-4-carbaldehyde (21). To a
solution of oxalyl chloride (50 mg, 0.37 mmol) in 1 mL of CH2-
Cl2 was added DMSO (36 mg, 0.47 mmol) at -78 °C. After
stirring for 10 min, alcohol E (75 mg, 0.31 mmol) in 0.5 mL of
CH2Cl2 was added dropwise. The mixture was stirred for
another 10 min, and then Et3N (104 mg, 1.02 mmol) was
added. After 20 min, the dry ice was removed and the solution
was stirred for 30 min and quenched with saturated aqueous
NaHCO3. The aqueous layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated to afford the crude
product. Flash chromatography on silica gel (7:3 (v/v) hexane/
EtOAc) provided compound 21 (58 mg, 76% yield) as a colorless
C: Rf ) 0.20 (5:5 (v/v) hexane/EtOAc); IR (neat, cm-1) 3465,
1
2988, 1453, 1375; H NMR (CDCl3, 600 MHz) δ 4.60 (d, J )
7.8 Hz, 1H), 4.37 (dd, J ) 2.4, 7.8 Hz, 1H), 4.24 (q, J ) 7.2 Hz,
1H), 4.23 (q, J ) 7.2 Hz, 1H), 3.86 (d, J ) 6.0 Hz, 1H), 3.50
(ddd, J ) 1.8, 7.5, 7.5 Hz, 1H), 2.60 (d, J ) 10.2 Hz, 1H), 2.23
(d, J ) 7.2 Hz, 1H), 1.47 (s, 3H), 1.42 (s, 3H), 1.29 (d, J ) 6.0
Hz, 3H), 1.28 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 130 MHz)
δ 170.8, 111.5, 78.3, 75.4, 72.7, 69.5, 61.5, 26.6, 25.7, 19.8, 14.1;
HRMS (CI) calcd for [C11H20O6 + Na]+ 271.1152, found
271.1154.
oil: Rf ) 0.23 (7:3 (v/v) hexane/EtOAc); IR (neat, cm-1) 2986,
1
1743; [R]25 ) +33° (c 1, CHCl3); H NMR (CDCl3, 270 MHz)
D
δ 9.79 (dd, J ) 1.5, 1.7 Hz, 1H), 4.39 (dq, J ) 6.4, 6.4 Hz, 1H),
4.31 (ddd, J ) 1.7, 1.7, 7.9 Hz, 1H), 4.08 (dd, J ) 1.7, 6.7 Hz,
1H), 3.94 (ddd, J ) 1.7, 1.7, 7.9 Hz, 1H), 1.50 (s, 6H), 1.40 (s,
3H), 1.36 (d, J ) 6.7 Hz, 3H), 1.35 (s, 3H); 13C NMR (CDCl3,
62.5 MHz) δ 201.7, 111.7, 108.5, 81.2, 75.8, 75.7, 72.6, 26.7,
26.6, 26.2, 25.4, 14.9; HRMS (CI) calcd for [C12H20O5 + Na]+
267.1203, found: 267.1206.
D: Rf ) 0.25 (5:5 (v/v) hexane/EtOAc); IR (neat, cm-1) 3464,
1
2986, 1451, 1378; H NMR (CDCl3, 270 MHz) δ 4.52 (d, J )
6.4 Hz, 1H), 4.30 (dd, J ) 5.2, 6.7 Hz, 1H), 4.24 (q, J ) 7.2 Hz,
1H), 4.23 (q, J ) 6.9 Hz, 1H), 3.91 (dq, J ) 3.7, 6.4 Hz, 1H),
3.54 (dd, J ) 3.7, 5.2 Hz, 1H), 3.04 (bs, 2H), 1.46 (s, 3H), 1.38
(s, 3H), 1.28 (t, J ) 7.2 Hz, 3H), 1.24 (d, J ) 6.2 Hz, 3H); 13C
NMR (CDCl3, 62.5 MHz) δ 171.8, 111.1, 79.4, 75.8, 74.9, 66.7,
61.8, 26.8, 25.4, 19.4, 14.0; HRMS (CI) calcd for [C11H20O6 +
Na]+ 271.1152, found 271.1162.
(E)-Ethyl-3-((2′R,3′S)-2′,2′-dimethyl-5′-((4′′S,5′′S)-2′′,2′′,5′′-
trimethyl-1′′,3′′-dioxolan-4′′-yl)-1,3-dioxolane-4′yl)acry-
late (6a). (Z)-Ethyl-3-((2′R,3′S)-2′,2′-dimethyl-5′-((4′′S,5′′S)-
2′′,2′′,5′′-trimethyl-1′′,3′′-dioxolan-4′′-yl)-1,3-dioxolane-
4′yl)acrylate (6c). To a solution of aldehyde 21 (50 mg, 0.21
mmol) in 1 mL of CH2Cl2 was added ylide (143 mg, 0.42 mmol)
at room temperature. After 3 h, the solvent was removed in
vacuo. The crude product was purified by flash chromatogra-
phy on silica gel (8:2 (v/v) hexane/EtOAc) providing a mixture
of E/Z-isomeric acetonides 6a,c in a 1.1:1 ratio (63 mg, 98%
yield) as a colorless oil: Rf ) 0.38 (8:2 (v/v) hexane/EtOAc);
IR (neat, cm-1) 2989, 1714; 1H NMR (mixture) (CDCl3, 270
MHz) δ 6.99 (dd, J ) 15.6, 4.3 Hz, 1H), 6.14 (dd, J ) 15.8, 1.8
Hz, 1H), 4.56 (ddd, J ) 7.5, 4.3, 1.8 Hz, 1H), 4.19 (q, J ) 7.1
Hz, 2H), 4.01 (dd, J ) 7.5, 6.2 Hz, 1H), 3.68 (dd, J ) 7.9, 7.5
Hz, 1H), 3.54 (dd, J ) 7.7, 7.7 Hz, 1H), 1.40 (s, 3H), 1.39 (s,
6H), 1.34 (d, J ) 5.9 Hz, 3H), 1.33 (s, 3H), 1.27 (t, J ) 7.1 Hz,
3H); 13C NMR (CDCl3, 67.5 MHz) δ 166.3, 145.0, 121.4, 110.4,
109.1, 83.1, 81.5, 79.3, 76.6, 60.5, 27.4, 27.0, 26.9, 26.8, 18.5,
14.3; HRMS (CI) calcd for [C16H26O4 + Na]+ 337.1622, found
337.1618.
(2S,3R)-Ethyl-2,2-dimethyl-5-((4S,5S)-2′,2′,5-trimethyl-
1′,3′-dioxolan-4′-yl)-1,3-dioxolane-4-carboxyate (20). To a
solution of diol C (120 mg, 0.49 mmol) in 4 mL of CH2Cl2 was
added 2,2-dimethoxypropane (0.61 mL, 4.9 mmol) and CSA
(18 mg, 10 mol %, 0.074 mmol) at room temperature. After 24
h, the reaction was quenched by adding saturated NaHCO3.
The aqueous layer was separated and extracted with Et2O,
and the combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and concentrated to afford the crude
product. Flash chromatography on silica gel (8:2 (v/v) hexane/
EtOAc) provided compound 20 (92 mg, 65% yield) as a colorless
oil: Rf ) 0.65 (7:3 (v/v) hexane/EtOAc); [R]25D +72° (c 1, CHCl3);
IR (neat, cm-1) 2931, 1746; 1H NMR (CDCl3, 270 MHz) δ 4.47
(d, J ) 8.2 Hz, 1H), 4.43 (dq, J ) 6.4, 6.4 Hz, 1H), 4.24 (q,
J ) 6.9 Hz, 1H), 4.23 (q, J ) 7.2 Hz, 1H), 4.19 (dd, J ) 2.0,
6.7 Hz, 1H), 4.01 (dd, J ) 1.7, 8.2 Hz, 1H), 1.51 (s, 3H), 1.49
(s, 3H), 1.42 (s, 3H), 1.39 (d, J ) 6.4 Hz, 3H), 1.37 (s, 3H),
1.29 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) δ 170.7,
111.5, 108.5, 77.6, 75.8, 75.6, 72.6, 61.4, 26.7, 26.7, 25.8, 25.5,
(E)-3-((4′R,5′S)-2′,2′-Dimethyl-5′-((4′′S,5′′S)-2′′,2′′,5′′-tri-
methyl-1′′,3′′-dioxolan-4′′-yl)-1′,3′-dioxolane-4′-yl)prop-2-
en-1-ol (F). 18 (Z)-3-((4′R,5′S)-2′,2′-Dimethyl-5′-((4′′S,5′′S)-
2′′,2′′,5′′-trimethyl-1′′,3′′-dioxolan-4′′-yl)-1′,3′-dioxolane-4′-
yl)prop-2-en-1-ol (G).18 To a solution of ester 6a,c (1.1:1 ratio
J. Org. Chem, Vol. 70, No. 24, 2005 9937

Gao and O’Doherty
of E/Z isomers) (65 mg, 0.20 mmol) in 1 mL of THF was added
DIBAL-H (0.60 mL, 1.0 M in hexanes, 4.0 mmol) dropwise at
-78 °C. After 30 min, the reaction was quenched by adding 1
mL of acetone and 3 mL of 20% sodium potassium tartrate
solution. The mixture was stirred for 30 min. The aqueous
layer was extracted with Et2O. The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, and
concentrated to afford the crude product. Flash chromatogra-
phy on silica gel (7:3 (v/v) hexane/EtOAc) provided allylic
alcohol F (26 mg, 46% yield) and G (25 mg, 45% yield) (91%
combined yield) as a colorless oil.
(3R,E)-1-((4′R,5′S)-2′,2′-Dimethyl-5′-((4′′S,5′′S)-2′′,2′′,5′′-
trimethyl-1′′,3′′-dioxolan-4′′-yl)-1′,3′-dioxolan-4′-yl)hexa-
1,5-dien-3-ol (25a). To a solution of (S,S)-27 (127 mg, 0.22
mmol) in 0.5 mL of CH2Cl2 was added aldehyde 24a (20 mg,
0.074 mmol) in 0.5 mL of CH2Cl2 dropwise at -10 °C. The
reaction flask was put in a freezer (-10 °C). After 20 h, the
reaction was diluted with EtOAc and quenched by adding 1
N HCl and the mixture was vigorously stirred at room
temperature for 15 min. The mixture was filtered through a
pad of Celite, and the layers were separated. The aqueous layer
was extracted with EtOAc. The combined organic layers were
washed with brine and dried over anhydrous Na2SO4, before
being concentrated to afford the crude product. Flash chro-
matography on silica gel (9:1 (v/v) hexane/EtOAc) provided
compound 25a (21 mg, 91% yield) as a colorless oil: Rf ) 0.25
(7:3 (v/v) hexane/EtOAc); IR (neat, cm-1) 3453, 2989, 1637;
F: Rf ) 0.20 (7:3 (v/v) hexane/EtOAc); IR (neat, cm-1) 3428,
2986; 1H NMR (CDCl3, 270 MHz) δ 6.06 (ddd, J ) 5.0, 5.0,
15.6 Hz, 1H), 5.70 (dddd, J ) 1.7, 1.7, 7.9, 15.5 Hz, 1H), 4.43-
4.33 (m, 2H), 4.19 (d, J ) 3.7 Hz, 2H), 3.94 (dd, J ) 1.8, 6.5
Hz, 1H), 3.59 (dd, J ) 2.0, 8.6 Hz, 1H), 1.53 (s, 3H), 1.45 (s,
3H), 1.42 (s, 3H), 1.37 (d, J ) 6.4 Hz, 3H), 1.36 (s, 3H); 13C
NMR (CDCl3, 67.5 MHz) δ 135.2, 127.2, 109.4, 108.6, 79.3,
78.1, 74.8, 72.7, 62.7, 27.2, 26.9, 26.8, 25.6, 15.1; HRMS (CI)
calcd for [C14H24O5 + Na]+ 295.1516, found 295.1513.
[R]25 +48° (c 1, CHCl3); 1H NMR (CDCl3, 600 MHz) δ 5.93
D
(dd, J ) 6.0, 15.6 Hz, 1H), 5.80 (ddd, J ) 7.8, 9.6, 17.4 Hz,
1H), 5.69 (dd, J ) 7.8, 15.6 Hz, 1H), 5.16 (bs, 1H), 5.14 (dd,
J ) 1.2, 3.0 Hz, 1H), 4.37 (dd, J ) 8.4, 8.4, 1H), 4.36 (dd, J )
6.0, 6.0, 1H), 4.23 (dd, J ) 5.4, 5.4 Hz, 1H), 3.93 (d, J ) 6.0
Hz, 1H), 3.58 (d, J ) 8.4 Hz, 1H), 2.37 (ddd, J ) 1.2, 7.8, 13.8
Hz, 1H), 2.25 (ddd, J ) 7.2, 7.8, 13.2 Hz, 1H), 1.52 (s, 3H),
1.44 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H), 1.35 (d, J ) 6.6 Hz,
3H); 13C NMR (CDCl3, 67.5 MHz) δ 137.7, 133.7, 127.0, 118.7,
109.5, 108.4, 79.4, 78.2, 74.9, 72.7, 70.5, 41.7, 27.2, 26.9, 26.8,
25.6, 15.1; HRMS (CI) calcd for [C17H28O5 + Na]+ 335.1829,
found 335.1823.
G: Rf ) 0.25 (7:3 (v/v) hexane/EtOAc); IR (neat, cm-1) 3423,
1
2986; [R]25 +59° (c 1, CHCl3); H NMR (CDCl3, 270 MHz) δ
D
5.94 (ddd, J ) 1.0, 6.7, 11.1 Hz, 1H), 5.53 (dddd, J ) 1.0, 1.0,
8.9, 9.9 Hz, 1H), 4.74 (ddd, J ) 1.0, 8.6, 8.6 Hz, 1H), 4.37 (dq,
J ) 6.4, 6.4 Hz, 1H), 4.25 (dd, J ) 6.9, 6.7 Hz, 2H), 3.89 (dd,
J ) 1.7, 6.7 Hz, 1H), 3.52 (dd, J ) 1.8, 8.7 Hz, 1H), 1.52 (s,
3H), 1.44 (s, 3H), 1.42 (s, 3H), 1.37 (d, J ) 6.5 Hz, 3H), 1.35
(s, 3H); 13C NMR (CDCl3, 67.5 MHz) δ 134.7, 128.1, 109.5,
108.5, 79.4, 74.5, 73.2, 72.7, 58.4, 27.2, 26.9, 26.7, 25.5, 14.9;
HRMS (CI) calcd for [C14H24O5 + Na]+ 295.1516, found
295.1513.
(3R,E)-1-((4′R,5′S)-2′,2′-Dimethyl-5′-((4′′S,5′′S)-2′′,2′′,5′′-
trimethyl-1′′,3′′-dioxolan-4′′-yl)-1′,3′-dioxolan-4′-yl)hexa-
1,5-dien-3-yl Acrylate (5a). To a solution of alcohol 5a (20
mg, 0.064 mmol) in 1 mL of CH2Cl2 was added acrylic acid
(18 µL, 0.26 mmol), DCC (52 mg, 0.26 mmol), and DMAP (2
mg, catalytic amount). After 3 h, the reaction mixture was
diluted with Et2O, filtered through a pad of Celite, and washed
with Et2O. The organic layer was washed with saturated
aqueous NaHSO4, saturated aqueous NaHCO3, and brine and
dried over anhydrous Na2SO4, before being concentrated to
afford the crude product. Flash chromatography on silica gel
(9:1 (v/v) hexane/EtOAc) provided ester 25a (19 mg, 83% yield)
(E)-3-((4′R,5′S)-2′,2′-Dimethyl-5′-((4′′S,5′′S)-2′′,2′′,5′′-tri-
methyl-1′′,3′′-dioxolan-4′′-yl)-1′,3′-dioxolane-4′-yl)acrylal-
dehyde (24a). To a solution of alcohol F (40 mg, 0.15 mmol)
in 3 mL of CH2Cl2 was added MnO2 (127 mg, 1.5 mmol) at
room temperature. After 4 h, the reaction mixture was filtered
through a pad of Celite and washed with EtOAc. The organic
layers were washed with brine, dried over anhydrous Na2SO4,
and concentrated to afford the crude product. Flash chroma-
tography on silica gel (8:2 (v/v) hexane/EtOAc) provided
aldehyde 24a (37 mg, 93% yield) as a white solid: mp ) 50-
as a colorless oil: Rf ) 0.50 (7:3 (v/v) hexane/EtOAc); IR (neat,
1
cm-1) 2986, 1731; [R]25 +40° (c 1, CHCl3); H NMR (CDCl3,
D
52 °C; Rf ) 0.51 (7:3 (v/v) hexane/EtOAc); IR (neat, cm-1) 2989,
600 MHz) δ 6.39 (dd, J ) 1.2, 17.4 Hz, 1H), 6.10 (dd, J ) 10.2,
17.4 Hz, 1H), 5.86 (dd, J ) 6.6, 15.6 Hz, 1H), 5.82 (dd, J )
1.2, 7.2 Hz, 1H), 5.75 (ddd, J ) 7.2, 7.2, 10.2 Hz, 1H), 5.70
(ddd, J ) 1.2, 7.2, 7.2 Hz, 1H), 5.42 (dd, J ) 6.0, 6.6 Hz, 1H),
5.11-5.07 (m, 2H), 4.36-4.33 (m, 2H), 3.89 (dd, J ) 2.4, 6.6
Hz, 1H), 3.57 (dd, J ) 2.4, 8.4 Hz, 1H), 3.21-3.17 (m, 1H),
2.44 (dd, J ) 6.6, 6.0 Hz, 1H), 1.51 (s, 3H), 1.43 (s, 3H), 1.41
(s, 3H), 1.36 (s, 3H), 1.33 (d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 165.2, 132.8, 132.7, 130.8, 129.7, 128.5, 118.3,
109.6, 108.4, 79.4, 78.0, 75.0, 72.8, 72.8, 38.8, 27.1, 26.9, 26.8,
25.6, 15.1; HRMS (CI) calcd for [C20H30O6 + Na]+ 389.1935,
found 389.1924.
1
1682; [R]25 +59 (c 1, CHCl3); H NMR (CDCl3, 270 MHz) δ
D
9.59 (d, J ) 7.7, Hz, 1H), 6.76 (dd, J ) 5.7, 15.8 Hz, 1H), 6.42
(ddd, J ) 1.2, 7.7, 15.6 Hz, 1H), 4.68 (ddd, J ) 1.2, 5.7, 8.7,
Hz, 1H), 4.42 (dq, J ) 6.5, 6.5 Hz, 1H), 3.97 (dd, J ) 1.2, 6.7
Hz, 1H), 3.66 (dd, J ) 1.2, 8.6 Hz, 1H), 1.53 (s, 3H), 1.48 (s,
3H), 1.43 (s, 3H), 1.39 (d, J ) 6.7 Hz, 3H), 1.37 (s, 3H); 13C
NMR (CDCl3, 67.5 MHz) δ 192.8, 151.6, 133.1, 110.7, 108.7,
79.4, 76.5, 74.5, 72.7, 26.9, 26.8, 26.6, 25.4, 14.8; HRMS (CI)
calcd for [C14H22O5 + Na]+ 293.1359, found 293.1368.
(Z)-3-((4′R,5′S)-2′,2′-Dimethyl-5′-((4′′S,5′′S)-2′′,2′′,5′′-tri-
methyl-1′′,3′′-dioxolan-4′′-yl)-1′,3′-dioxolane-4′-yl)acrylal-
dehyde (24c). To a solution of alcohol G (38 mg, 0.14 mmol)
in 3 mL of CH2Cl2 was added MnO2 (122 mg, 1.4 mmol) at
room temperature. After 5 h, the reaction mixture was filtered
through a pad of Celite and washed with EtOAc. The organic
layers were washed with brine, dried over anhydrous Na2SO4,
and concentrated to afford the crude product. Flash chroma-
tography on silica gel (8:2 (v/v) hexane/EtOAc) provided
aldehyde 24c (35 mg, 92% yield) as a colorless oil: Rf ) 0.45
(6R)-5,6-Dihydro-6-(E)-2′-((4′R,5′S)-2′,2′-dimethyl-5′-
((4′′S,5′′S)-2′′,2′′,5′′-trimethyl-1′′,3′′-dioxolan-4′′-yl)-1′,3′-di-
oxolan-4′-yl)pyran-2-one (26a). To a solution of triene 5a
(18 mg, 0.051 mmol) in 3 mL of CH2Cl2 was added Grubbs
catalyst (9 mg, 0.01 mmol, 10 mol %) in 2 mL of CH2Cl2. The
reaction was heated at reflux for 2 h. Solvent was removed
under reduced pressure, and the residue was purified by flash
chromatography on silica gel (7:3 (v/v) hexane/EtOAc) provid-
ing lactone 26a (13 mg, 77% yield) as a colorless oil: Rf ) 0.14
(7:3 (v/v) hexane/EtOAc); IR (neat, cm-1) 2989, 1682; [R]25
D
+60° (c 1, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 10.17 (d, J )
7.9 Hz, 1H), δ 6.52 (dd, J ) 8.2, 11.4 Hz, 1H), 6.10 (ddd, J )
1.2, 7.9, 11.4 Hz, 1H), 5.26 (ddd, J ) 1.2, 8.7, 8.7 Hz, 1H),
4.42 (dq, J ) 6.4, 6.4 Hz, 1H), 3.92 (dd, J ) 1.2, 6.7 Hz, 1H),
3.64 (dd, J ) 1.2, 8.6 Hz, 1H), 1.53 (s, 3H), 1.49 (s, 3H), 1.46
(s, 3H), 1.40 (d, J ) 6.2 Hz, 3H), 1.36 (s, 3H); 13C NMR (CDCl3,
67.5 MHz) δ 191.5, 146.2, 133.0, 110.8, 108.8, 79.5, 73.9, 73.4,
72.7, 27.2, 27.0, 26.7, 25.5, 14.9; HRMS (CI) calcd for [C14H22O5
+ Na]+ 293.1359, found 293.1368.
(7:3 (v/v) hexane/EtOAc); IR (neat, cm-1) 2983, 1742; [R]25
D
+133° (c 0.4, CHCl3); 1H NMR (CDCl3, 600 MHz) δ 6.89 (ddd,
J ) 1.2, 3.0, 9.6 Hz, 1H), 6.05 (ddd, J ) 1.2, 1.2, 9.6 Hz, 1H),
5.98 (dd, J ) 6.0, 15.6 Hz, 1H), 5.85 (dd, J ) 7.2, 15.0 Hz,
1H), 4.95 (ddd, J ) 4.8, 6.0, 6.0 Hz, 1H), 4.41 (dd, J ) 7.8, 7.8
Hz, 1H), 4.39 (dd, J ) 6.9, 6.9 Hz, 1H), 3.95 (d, J ) 6.6 Hz,
1H), 3.57 (d, J ) 8.4 Hz, 1H), 2.49 (ddd, J ) 4.8, 5.4, 18.6 Hz,
1H), 2.43 (dddd, J ) 2.4, 2.4, 10.8, 18.0 Hz, 1H), 1.52 (s, 3H),
1.45 (s, 3H), 1.42 (s, 3H), 1.37 (d, J ) 7.8 Hz, 3H), 1.37 (s,
9938 J. Org. Chem., Vol. 70, No. 24, 2005

Asymmetric Synthesis of Anamarine and Its Analogues
3H); 13C NMR (CDCl3, 125 MHz) δ 163.5, 144.4, 131.5, 130.9,
121.6, 109.8, 108.4, 79.4, 77.6, 77.1, 74.5, 72.7, 29.6, 27.1, 26.9,
26.7, 25.5, 15.0; HRMS (CI) calcd for [C18H26O6 + Na]+
361.1622, found 361.1621.
7.0 Hz, 1H), 4.99-4.90 (m, 1H), 4.91 (dq, J ) 6.4, 6.4 Hz, 1H),
2.47-2.41 (m, 2H), 2.12 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.02
(s, 3H), 1.17 (d, J ) 6.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
δ 170.0, 169.8, 169.7, 169.6, 163.4, 144.4, 133.0, 125.6, 121.5,
75.8, 71.9, 71.6, 70.5, 67.3, 29.1, 21.0, 20.9, 20.8, 20.6, 15.8;
HRMS (CI) calcd for [C20H26O10 + Na]+ 449.1419, found
449.1424.
Anamarine (1a). A solution of 10% aqueous HCl and THF
(1:1, 1.0 mL) was added to a flask containing acetonide 26a (8
mg, 0.024 mmol). The mixture was heated at 65 °C for 20 min,
and the solvent was removed at reduced pressure. The residue
was dissolved in 1.0 mL of pyridine, and then Ac2O (0.1 mL)
and a catalytic amount of DMAP were added. After 20 h, solid
NaHCO3 was added, diluted with EtOAc, and then filtered
through a pad of Celite. The solvent was removed under
reduced pressure, and the residue was purified by flash
chromatography on silica gel (50:50 (v/v) hexane/EtOAc)
providing anamarine (8 mg, 85% yield) as a white solid:
mp ) 109-111 °C; Rf ) 0.15 (1:1 (v/v) hexane/EtOAc); IR (neat,
cm-1) 2986, 1742; [R]25D +17° (c 0.3, CHCl3); 1H NMR (CDCl3,
270 MHz) δ 6.88 (ddd, J ) 3.5, 5.2, 9.9 Hz, 1H), 6.05 (ddd,
J ) 1.7, 1.7, 9.9 Hz, 1H), 5.88-5.74 (m, 2H), 5.36 (dd, J ) 5.2,
7.2 Hz, 1H), 5.30 (dd, J ) 3.5, 7.2 Hz, 1H), 5.17 (dd, J ) 3.5,
Acknowledgment. We are grateful to NIH (GM-
63150) and NSF (CHE-0415469) for the support of our
research program and NSF-EPSCoR (0314742) for a 600
MHz NMR at WVU.
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds
can be found in the Supporting Information. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO051681P
J. Org. Chem, Vol. 70, No. 24, 2005 9939